CN107674086A - Polycyclic carbamoylpyridone compound and its medicinal usage - Google Patents

Abstract

Compounds for the treatment of human immunodeficiency virus (HIV) infection are disclosed. The compound has the following formula (I): Stereoisomers and pharmaceutically acceptable salts thereof are included, wherein R ¹ , X, W, Y ¹ , Y ² , Z ¹ and Z ⁴ are as defined herein. Also disclosed are methods relating to the preparation and use of such compounds and pharmaceutical compositions comprising such compounds.

Description

Polycyclic-carbamoylpyridone compounds and their pharmaceutical use

This application is a Chinese patent application that the international application PCT/US2013/076367 has entered the Chinese national phase (application number is 201380073134. Its medicinal use”) divisional application.

Cross References to Related Applications

This patent application claims under 35 U.S.C. §119(e) U.S. Provisional Patent Application No. 61/745,375 filed December 21, 2012, U.S. Provisional Patent Application No. 61/788,397 filed March 15, 2013, and Benefit of U.S. Provisional Patent Application No. 61/845,803, filed July 12, 2013. The entire contents of the aforementioned applications are incorporated herein by reference.

Background technique

field of invention

Compounds, compositions and methods for treating human immunodeficiency virus (HIV) infection are disclosed. In particular, novel polycyclic carbamoylpyridone compounds and methods for their preparation and use as therapeutic or prophylactic agents are disclosed.

Description of related technologies

Human immunodeficiency virus infection and related diseases are major public health problems worldwide. Human immunodeficiency virus type 1 (HIV-1) encodes three enzymes required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptases and proteases are widely used and have been shown to be effective, especially when used in combination, the development of toxic and resistant strains limits their usefulness (Palella, et al. N. Engl. J Med (1998) 338:853-860; Richman, D.D. Nature (2001) 410:995-1001).

The pregnane X receptor (PXR) is a nuclear receptor that is one of the key regulators of enzymes involved in the metabolism and elimination of small molecules from the body. Activation of PXR is known to upregulate or induce the production of metabolic enzymes such as cytochrome P450 3A4 (CYP3A4) and enzymes involved in transport such as OATP2 in the liver and intestine (Endocrine Reviews (2002) 23(5):687-702). When a drug causes the upregulation of these and other enzymes by the activation of PXR, this may reduce the absorption and/or exposure of co-administered drugs that are sensitive to the upregulated enzymes. In order to minimize the risk of drug-drug interactions of this type, it is desirable to minimize the activation of PXR. Further, PXR is known to be activated by many different types of molecules (Endocrine Reviews (2002) 23(5):687-702). Therefore, it is important to test and minimize PXR activation for drugs that are to be co-administered with other drugs.

Transporters have been identified to play a role in pharmacokinetics, safety and efficacy properties or drugs, and certain drug-drug interactions are mediated by transporters. See, Giacomini KM, et al. ""Membrane transporters in drug development," Nat. Rev Drug Discov. 9:215-236, 2010; Zhang L, et al. "Transporter-Mediated Drug-Drug Interactions," Clin.Pharm. Ther.89(4):481-484(2011). A transporter (organic cation transporter 2 (OCT2; SLC22A2)) is a member of the solute carrier (SLC) superfamily of transporters, and is mainly located near the kidney on the basolateral membrane of terminal tubules. OCT2, involved in apically expressed multidrug and toxin excretion (MATE) transporters 1 and 2-K, is thought to form the major cation secretion pathway in the kidney and has been shown to transport endogenous substances including creatinine OCT2 inhibition can lead to increased levels of serum creatinine and possibly increased levels of other OCT2 substances. It is also important to test and reduce OCT2 inhibition by drugs.

The goal of antiretroviral therapy is to achieve viral suppression in HIV-infected patients. Treatment guidelines published by the United States Department of Health and Human Services provide that achieving viral suppression requires the use of combination therapy, ie several drugs from at least two or more drug classes. (Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.Section accessed March 14, 2013.). Additionally, treatment decisions regarding HIV-infected patients are complicated when the patient requires treatment for other medical conditions (Id., at E-12). Because the standard of care requires the use of many different drugs to suppress HIV, as well as to treat other conditions that patients may experience, the possibility of drug interactions is a criterion for selecting a drug regimen. As such, there is a need for antiretroviral therapies with a reduced potential for drug interactions. Therefore, there is a need for new agents that inhibit HIV replication and minimize PXR activation when co-administered with other drugs.

Brief description of the invention

The present invention relates to novel polycyclic carbamoylpyridone compounds having antiviral activity, including their stereoisomers and pharmaceutically acceptable salts, and the use of such compounds in the treatment of HIV infection. The compounds of the invention are useful for inhibiting the activity of HIV integrase and for reducing HIV replication.

In one embodiment of the present invention there is provided a compound of formula (I):

or its stereoisomer or pharmaceutically acceptable salt,

in:

X is -O- or -NZ ³ - or -CHZ ³ -;

W is -CHZ ² -;

Z ¹ , Z ² and Z ³ are each independently hydrogen or C _1-3 alkyl, or wherein Z ¹ and Z ² or Z ¹ and Z ³ are combined to form -L-, wherein L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -or-C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, wherein at least one group of Z ¹ and Z ² or Z ¹ and Z ³ together form -L-;

Z ⁴ is a bond, -CH ₂ - or -CH ₂ CH ₂ -;

Y ¹ and Y ² are each independently hydrogen, C _1-3 alkyl or C _1-3 haloalkyl;

R is phenyl substituted with ^one to three halogens; and

Each R ^a is independently hydrogen, halogen, hydroxy, or C _1-4 alkyl.

In another embodiment of the present invention there is provided a compound having the following formula (I):

or its stereoisomer or pharmaceutically acceptable salt,

in:

X is -O- or -NZ ³ - or -CHZ ³ -;

W is -O- or -NZ ² - or -CHZ ² -;

Z ¹ , Z ² and Z ³ are each independently hydrogen or C _1-3 alkyl, or wherein Z ¹ and Z ² or Z ¹ and Z ³ are combined to form -L-, wherein L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, - C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ NR ^a C(R ^a ) ₂ -or-C(R ^a ) ₂ NR ^a SO ₂ C(R ^a ) ₂ −;

Z ⁴ is a bond or -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ OCH ₂ -, -CH ₂ NR ^a CH ₂ -, -CH ₂ SCH ₂ -,- CH ₂ S(O)CH ₂ -or -CH ₂ SO ₂ CH ₂ -;

Y and Y are each independently ^hydrogen , C ^1-3 alkyl or C _1-3 haloalkyl, or Y and Y together with the carbon atoms to which they are attached form ^a carbocyclic ring having ₃ to ⁶ ring atoms, or ^a heterocyclic ring having 3 to 6 ring atoms, wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more R;

R is optionally substituted aryl or optionally substituted heteroaryl ^; and

each R is independently hydrogen, halogen, hydroxy, ^or _C1-4 alkyl, or wherein two R groups together with the carbon atoms to which they are attached form C ⁼ O, and

wherein at least ^{one of} : (i) Z1 and Z2 or Z1 and Z3 together form -L-; or (ii ^{) Y1} and ^Y2 together with the carbon atom to which they are attached form ^a carbocyclic or heterocyclic rings having 3 to 6 ring atoms.

In another embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient.

The present invention also provides the use of a pharmaceutical composition as described above for the treatment of HIV infection in a human suffering from or at risk of developing infection.

In another embodiment, there is provided a method of using a compound of formula (I) in therapy. In particular, there is provided a method of treating HIV virus proliferation in a mammal (such as a human), treating AIDS, or delaying the onset of symptoms of AIDS or ARC, comprising administering to said mammal a compound having formula (I), or Stereoisomers or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers, diluents or excipients.

In another embodiment there is disclosed the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment of HIV infection in a human having or at risk of having the infection.

In another embodiment, the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of HIV infection in a human suffering from or at risk of having the infection is disclosed .

In another embodiment, an article of manufacture comprising a composition effective for treating HIV infection; and packaging material comprising a label indicating that the composition is useful for treating HIV infection is disclosed. Exemplary compositions include a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the invention.

In yet another embodiment, a method of inhibiting HIV replication is disclosed. The method comprises exposing the virus to an effective amount of a compound of formula (I) or a salt thereof under conditions in which HIV replication is inhibited.

In another embodiment, the use of a compound of formula (I) to inhibit the activity of HIV integrase is disclosed.

In another embodiment, the use of a compound of formula (I) or a salt thereof to inhibit HIV replication is disclosed.

Other embodiments, objects, features and advantages will be set forth in the detailed description of the embodiments that follow, and in part will be obvious from the description of the claimed invention, or may be learned by practice of the claimed invention. These objects and advantages will be realized and obtained by the method and composition particularly pointed out in the written description and claims hereof. The foregoing summary should be understood as being considered a brief and general summary of some of the embodiments disclosed herein, provided solely for the benefit and convenience of the reader, and not intended to limit in any way the legally conferred scope or equivalents of the appended claims. range of things.

Detailed description

In the following description, certain details are set forth in order to provide a detailed understanding of various embodiments of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these details. It should be understood that the following description of several embodiments is to be considered as an illustration of the claimed subject matter, and that the appended claims are not intended to be limited to the specific embodiments set forth. Headings used throughout the specification are provided for convenience only and should not be construed as limiting the claims in any way. Embodiments set forth under any heading may be combined with embodiments set forth under any other heading.

definition

Throughout the specification and claims, unless the context requires otherwise, the term "comprise" and variations such as "comprises" and "comprising" shall be construed in an open, inclusive sense. , which is interpreted as "including without limitation".

Reference throughout this specification to "one embodiment" or "an embodiment" means that a said particular feature, structure or characteristic relating to the embodiment is included in at least one embodiment of the invention. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout the specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner in one or more embodiments.

Unless the context requires otherwise, references throughout the specification to "compounds of formula (I)" or "compounds of formula (I)" refer to all embodiments of formula (I), including for example compounds of formula: (II- A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F) , (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), ( IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV- BG) and (IV-BH), and specific compounds disclosed herein.

"Amino" refers to a _-NH2 group.

"Cyano" refers to a -CN group.

"Hydroxy" means an -OH group.

"Imido" refers to the =NH substituent.

"Nitro" refers to a _-NO2 group.

"Oxo" refers to a =O substituent.

"Thio" refers to the =S substituent.

"Alkyl" means a straight or branched chain hydrocarbon consisting only of carbon and hydrogen atoms, saturated or unsaturated (ie, containing one or more double and/or triple bonds), having from one to twelve carbon atoms (C ₁ -C ₁₂ alkyl), preferably one to eight carbon atoms (C ₁ -C ₈ alkyl) or one to six carbon atoms (C ₁ -C ₆ alkyl), and it is represented by a single bonded to the rest of the molecule, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl ( tert-butyl), 3-methylhexyl, 2-methylhexyl, vinyl, prop-1-enyl, but-1-enyl, pent-1-enyl, pent-1,4-dienyl , Ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkyl groups may be optionally substituted unless specifically stated otherwise in the specification.

"Alkylene" or alkylene chain" means a straight or branched divalent hydrocarbon chain consisting only of carbon and hydrogen, saturated or unsaturated ( That is, containing one or more double bonds and/or triple bonds), and having one to twelve carbon atoms, such as methylene, vinyl, propenyl, n-butenyl, vinylidene, propenylene, n-butenylene, propynyl, n-butynyl, etc. The alkylene chain is attached to the rest of the molecule by a single or double bond, and to the radical by a single or double bond. The point of attachment to the rest of the molecule and the group may be via one carbon or any two carbons within the chain. Unless specifically stated otherwise in the specification, the alkylene chain may be optionally substituted.

"Alkoxy" means a radical of the formula -OR _A where _RA is an alkyl group as defined above containing one to twelve carbon atoms. Unless specifically stated otherwise in the specification, alkoxy groups may be optionally substituted.

"Alkylamino" means a radical of the formula -NHR _A or -NR _A R _A wherein each R _A is independently an alkyl group as defined above containing one to twelve carbon atoms. Unless specifically stated otherwise in the specification, the alkylamino group may be optionally substituted.

"Thioalkyl" means a radical of the formula -SR _A where _RA is an alkyl group as defined above containing one to twelve carbon atoms. Unless specifically stated otherwise in the specification, thioalkyl groups may be optionally substituted.

"Aryl" refers to a monocyclic hydrocarbon ring system radical comprising hydrogen and 6 to 18 carbon atoms. Aryl groups include, but are not limited to, aryl groups derived from benzene. Unless specifically stated otherwise in the specification, the term "aryl" or the prefix "ar-" (eg, "aralkyl") is meant to include optionally substituted aryl groups.

"Aralkyl" means a group of formula -RB _{- RC} , wherein _RB is an alkylene chain as defined above and _Rc is one or more aryl groups as defined above, eg benzyl. Unless specifically stated otherwise in the specification, aralkyl groups may be optionally substituted.

"Cycloalkyl" or "carbocycle" refers to a stable non-aromatic monocyclic hydrocarbon radical consisting only of carbon and hydrogen atoms, having three to fifteen carbon atoms, preferably three to ten carbon atoms, and which be saturated or unsaturated and attached to the rest of the molecule by a single bond. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Unless specifically stated otherwise in the specification, cycloalkyl groups may be optionally substituted.

"Cycloalkylalkyl" means a radical of formula _-RB RD where _RB is an _alkylene chain as defined above and _RD is cycloalkyl as defined above. Unless specifically stated otherwise in the specification, cycloalkylalkyl groups may be optionally substituted.

"Halo" or halogen" refers to bromo, chloro, fluoro or iodo.

"Haloalkyl" means an alkyl group as defined above which is substituted by one or more halo groups as defined above, for example trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoro Ethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromomethyl, etc. Unless specifically stated otherwise in the specification, haloalkyl groups can be optionally substituted.

"Heterocyclyl" or heterocyclic ring" refers to a stable 3- to 18-membered non-aromatic ring group consisting of two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen and sulfur Composition. In the embodiments disclosed herein, the heterocyclyl is a monocyclic ring system; and the heterocyclyl can be partially or fully saturated. Examples of such heterocyclyl include, but are not limited to, dioxolanyl, thienyl , [1,3] dithianyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl ), tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl and 1,1-dioxo-thiomorpholinyl. Unless otherwise specified in the specification otherwise the heterocyclyl group may be optionally substituted.

"N-Heterocyclyl" means a heterocyclyl group as defined above containing at least one nitrogen and wherein the point of attachment of the heterocyclyl group to the rest of the molecule is through the nitrogen atom in the heterocyclyl group. Unless specifically stated otherwise in the specification, N-heterocyclyl groups may be optionally substituted.

"Heterocyclylalkyl" means a radical of the formula -RB R _E , wherein _{R B} is an alkylene chain as defined above and _RE is a heterocyclyl as defined above, and if the heterocyclyl is nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkyl at said nitrogen atom. Unless specifically stated otherwise in the specification, heterocyclylalkyl groups can be optionally substituted.

"Heteroaryl" refers to a 5- to 14-membered monocyclic ring system group containing hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from nitrogen, oxygen and sulfur. Examples include, but are not limited to, azepinyl, furyl, furanonyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxirane Base, 1-oxidized pyridinyl (oxidopyridinyl), 1-oxidized pyrimidinyl (oxidopyrimidinyl), 1-oxidized pyrazinyl, 1-oxidized pyridazinyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazine thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thiophenyl and thienyl. Unless specifically stated otherwise in the specification, heteroarylalkyl groups may be optionally substituted.

"N-Heteroaryl" means a heteroaryl group as defined above containing at least one nitrogen and wherein the point of attachment of the heteroaryl group to the rest of the molecule is through the nitrogen atom in the heteroaryl group. Unless specifically stated otherwise in the specification, N-heteroaryl groups may be optionally substituted.

"Heteroarylalkyl" means a radical of the formula -RB R _F where _RB is an alkylene chain as defined above and R _F is heteroaryl as defined above _. Unless specifically stated otherwise in the specification, heteroarylalkyl groups can be optionally substituted. As used herein, the term "substituted" refers to any of the above groups (i.e., alkyl, alkylene, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cyclo alkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocycloalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl), wherein at least one hydrogen atom is bonded Bond substitution by non-hydrogen atoms such as, but not limited to: halogen atoms such as F, Cl, Br, and I; oxygen atoms in groups such as hydroxyl, alkoxy, and ester groups; groups such as sulfur Sulfur atom in alcohol, thioalkyl, sulfone, sulfonyl and sulfoxide groups; groups such as amine, amide, alkylamine, dihydrocarbylamine, arylamine, alkylarylamine, diaryl Nitrogen atoms in amines, N-oxides, imides, and enamines; groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylmethyl silicon atoms in silyl groups; and other heteroatoms in various other groups. "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by hypervalent bonds (e.g., double or triple bonds) to heteroatoms such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and Groups such as nitrogen in imines, oximes, hydrazones, and nitriles. For example, "substituted" includes any of the above groups, wherein one or more hydrogen atoms are replaced by the following groups: -NR _G R _H , -NR _G C(=O)R _H , -NR _G C(= O)NR _G R _H , -NR _G C(=O)OR _H , -NR _G C(=NR _g )NR _G R _H , -NR _G SO ₂ R _H , -OC(=O)NR _G R _H , -OR _G , -SR _G , -SOR _G , -SO ₂ R _G , -OSO ₂ R _G , -SO ₂ OR _G , =NSO ₂ R _G and -SO ₂ NR _G R _H . "Substituted" also means any of the above groups, wherein one or more hydrogen atoms are replaced by the following groups: -C(=O)R _G , -C(=O)OR _G , -C(=O) NR _G R _H , -CH ₂ SO ₂ R _G , -CH ₂ SO ₂ NR _G R _H . In the foregoing, R _G and R _H are the same or different, independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkane radical, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl. "Substituted" further means any of the above groups, wherein one or more hydrogen atoms are replaced by a bond to: amino, cyano, hydroxyl, imino, nitro, oxo, thio, halo , Alkyl, Alkoxy, Alkylamino, Thioalkyl, Aryl, Aralkyl, Cycloalkyl, Cycloalkylalkyl, Haloalkyl, Heterocyclyl, N-Heterocyclyl, Heterocyclyl Alkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl. In addition, each of the aforementioned substituents may also be optionally substituted with one or more of the aforementioned substituents.

The term "protecting group" as used herein refers to a labile chemical moiety known in the art to protect reactive groups (including but not limited to hydroxyl and amino groups) from undesired reactions during synthetic procedures. Hydroxy and amino groups protected with protecting groups are referred to herein as "protected hydroxy" and "protected amino", respectively. Protecting groups are often used selectively and/or orthogonally to protect sites during reactions at other reactive sites and can then be removed leaving the unprotected group intact or participating in further reactions. Protecting groups as known in the art are generally described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Typically, groups are protected or exist as precursors that are inert to reactions that modify other regions of the parent molecule at appropriate times to convert them into their final groups. Other representative protecting or precursor groups are discussed in Agrawal, et al., Protocols for Oligonucleotide Conjugates, Eds, Humana Press; New Jersey, 1994; Vol. 26 pp. 1-72. Examples of "hydroxyl protecting groups" include, but are not limited to, tert-butyl, tert-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloro Ethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl, diphenyl- Methyl, p-nitrobenzyl, triphenylmethyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyl-diphenylsilyl (TBDPS), triphenylsilyl, benzoylformate, acetate, chloroacetate, trichloroacetate, trifluoroacetate, pivaloate, benzoic acid ester, p-phenylbenzoate, 9-fluorenylmethyl carbonate, mesylate and tosylate. Examples of "amino protecting groups" include, but are not limited to, carbamate protecting groups such as 2-trimethyl-silylethoxycarbonyl (Teoc), 1-methyl-1-(4-biphenyl )-ethoxy-carbonyl (Bpoc), tert-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz ); amide-protecting groups such as formyl, acetyl, trichloroacetyl, benzoyl, and nitrophenylacetyl; sulfonamide-protecting groups such as 2-nitrobenzenesulfonyl; and imines and cyclic Imine protecting groups such as phthalimido and dithiasuccinyl.

The invention disclosed herein is also meant to cover all pharmaceutically acceptable compounds of formula (I) which are isotopically labeled by substituting one or more atoms with atoms having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I and ¹²⁵ I. These radiolabeled compounds can be used to determine or measure the effectiveness of the compounds by characterizing, for example, the site or mode of action or binding affinity to a pharmacologically important site of action. Certain isotopically-labeled compounds of formula (I), such as those incorporating radioactive isotopes, are useful in drug and/or substrate tissue distribution studies. The radioisotopes tritium (ie ³ H) and carbon 14 ( ¹⁴ C) are particularly useful for this purpose due to their ease of incorporation and alternate means of detection.

Substitution with heavy isotopes such as deuterium (ie ² H) may confer certain therapeutic advantages resulting from greater metabolic stability. For example, in vivo half-life can be increased or dosage requirements can be decreased. Thus, in some cases, heavy isotopes may be preferred.

Substitution by positron-emitting isotopes, such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N, can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Isotope-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the examples below, using an appropriate isotope-labeled reagent instead of the non-labeled reagent used above.

The invention disclosed herein is also meant to encompass in vivo metabolites of the disclosed compounds. Such products may be obtained, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, mainly due to enzymatic processes. Accordingly, the invention includes compounds produced by a method comprising administering a compound of the invention to a mammal for a period of time sufficient to produce its metabolites. Such products are typically produced by administering a radiolabeled compound of the invention to an animal (e.g., rat, mouse, guinea pig, monkey, or human) in a detectable amount for a time sufficient to allow metabolism to occur and release from urine, blood, or Transformation products were isolated from other biological samples for identification.

"Stable compound" and "stable structure" are meant to refer to a compound that is sufficiently robust (enhanced) to be isolated to a useful degree of purity from a reaction mixture and formulated as an effective therapeutic agent. "Mammal" includes humans and domestic animals such as laboratory animals and domestic pets (eg, cats, dogs, pigs, cattle, sheep, goats, horses, rabbits) and non-domestic animals such as wild animals and the like.

"Optional" or "optionally" means that the subsequently stated time of event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group may be substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.

"Pharmaceutically acceptable carrier, diluent or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, glidant, Sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.

"Pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and that possesses (or can be converted into a form that possesses the pharmacological activity of the parent compound) the desired pharmacological activity. Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include those derived from suitable bases such as alkali metals (e.g. sodium), alkaline earth metals (e.g. magnesium), ammonium and NX ₄ ⁺ (wherein X is C ₁ -C ₄ alkyl ) of salt. Pharmaceutically acceptable salts of nitrogen or amino groups include, for example, salts of organic carboxylic acids, organic sulfonic acids, and inorganic acids such as acetic acid, benzoic acid, camphorsulfonic acid, citric acid, glucoheptonic acid, gluconic acid , lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, mandelic acid, isethionic acid, lactobionic acid succinic acid, 2-naphthalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid acid and trimethylacetic acid; said organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; said inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and sulfamic acid acid. Pharmaceutically acceptable salts of hydroxy compounds include the anion of said compound in combination with suitable ones such as Na ⁺ and NX ₄ ⁺ (wherein X is independently selected from H or C ₁ -C ₄ alkyl). Pharmaceutically acceptable salts also include salts formed by substitution with metal ions, such as alkali metal ions, alkaline earth metal ions, aluminum ions, when acidic protons are present in the parent compound; or with organic bases such as diethanolamine, triethanolamine, N -Salts formed by coordination with methylglucamine or the like. Also included in this definition are ammonium and substituted or quaternized ammonium salts. A representative non-limiting list of pharmaceutically acceptable salts can be found in SM Berge et al., J. Pharma Sci., 66(1), 1-19 (1977), and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st ed., Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), at p. 732, Table 38-5, both of which are hereby incorporated by reference.

For therapeutic use, the salts of the active ingredients of the compounds disclosed herein are generally pharmaceutically acceptable, ie, they are salts derived from physiologically acceptable acids or bases. However, salts of acids or bases which are not found to be pharmaceutically acceptable may also be useful, for example, in the preparation or purification of a compound of formula (I) or another compound of the invention. All salts, whether derived from physiologically acceptable acids or bases or not, are within the scope of the present invention.

Metal salts are generally prepared by reacting metal hydroxides with compounds of the invention. Examples of metal salts prepared in this way are salts containing Li ⁺ , Na ⁺ and K ⁺ . Less soluble metal salts can be precipitated from solutions of more soluble salts by adding a suitable metal compound.

Additionally, salts can be formed by the addition _of certain organic and inorganic acids, such as HCl, _HBr , _H2SO4 , _H3PO4 , or organic sulfonic acids, to a basic center, usually an amine. Finally, it is to be understood that the compositions herein include the compounds disclosed herein in non-ionized as well as in zwitterionic form and in combination with stoichiometric amounts of water as hydrates.

Crystallization generally results in solvates of the compounds of the invention. The term "solvate" as used herein refers to an aggregate comprising one or more molecules of a compound of the invention with one or more solvent molecules. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Accordingly, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms. The compounds of the present invention may be true solvates, while in other cases, the compounds of the present invention may retain only extrinsic water or be a mixture of water plus some extrinsic solvent.

A "pharmaceutical composition" refers to a formulation of a compound of the invention and a vehicle generally accepted in the art for the delivery of a biologically active compound to a mammal, such as a human. Such medium includes all pharmaceutically acceptable carriers, diluents or excipients thereof. "Effective amount" or "therapeutically effective amount" refers to an amount of a compound according to the invention which, when administered to a patient in need thereof, is sufficient to produce effective treatment of the disease-state, condition or disorder for which the compound acts. Such amounts are sufficient to elicit the biological or medical response in the tissue system or patient sought by the researcher or clinician. The amount of a compound according to the invention constituting a therapeutically effective amount will vary depending on factors such as the compound and its biological activity, the composition used for administration, time of administration, route of administration, rate of excretion of the compound, duration of treatment, The type of disease-state or condition to be treated and its severity, the drugs used in combination or co-administration with the compounds of the invention, the patient's age, weight, general health, sex and diet. Such a therapeutically effective amount can be routinely determined by those of ordinary skill in the art having regard to their own knowledge, the state of the art and this disclosure.

The term "treatment" as used herein is used to refer to administration of a compound or composition according to the present invention to alleviate or eliminate symptoms of HIV infection and/or reduce viral load in a patient. The term "treatment" also encompasses the administration of a compound or composition according to the invention to prevent the onset of symptoms and and/or preventing the virus from reaching detectable levels in the blood, and administering a compound or composition according to the invention to prevent perinatal transmission of HIV from the mother by administering to the mother prior to delivery and to the child in the first days after birth transmitted to infants.

The term "antiviral agent" as used herein refers to an agent (compound or organism) effective to inhibit virus formation and/or replication in humans, including, but not limited to, interference with host or Reagents of viral mechanisms.

The term "inhibitor of HIV replication" as used herein is meant to refer to an agent capable of reducing or eliminating the ability of HIV to replicate in a host cell, whether in vitro, ex vivo or in vivo.

The compounds of the present invention or their pharmaceutically acceptable salts may contain one or more asymmetric centers and thus may generate enantiomers, diastereomers, and may be defined as (R)- or ( S)- or other stereoisomeric forms of (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or can be prepared using conventional methods Examples include chromatography and fractional crystallization. Conventional methods for the preparation/isolation of the individual enantiomers include chiral synthesis from suitable optically pure precursors or the use of, for example, chiral high pressure liquid chromatography (HPLC) for the racemate (or for the exogenous synthesis of a salt or derivative). racemate) resolution. When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise indicated, it is meant that the compounds include both E and Z geometric isomers. Furthermore, all tautomeric forms are also meant to be included.

"Stereoisomer" refers to compounds composed of the same atoms bonded by the same bonds but with different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof, and includes "enantiomers", which refers to two stereoisomers whose molecules are non-superimposable mirror images of each other.

"Tautomer" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. The present invention includes tautomers of any of said compounds.

"Prodrug" refers to a compound chemically designed to effectively release the parent drug after overcoming the biological barrier of oral delivery. In some embodiments, the present invention includes prodrugs of compounds of formula (I).

compound

As mentioned above, in one embodiment of the present invention, there is provided a compound having antiviral activity, said compound having the following formula (I):

or its stereoisomer or pharmaceutically acceptable salt,

in:

X is -O- or -NZ ³ - or -CHZ ³ -;

W is -CHZ ² -;

Z ¹ , Z ² and Z ³ are each independently hydrogen or C _1-3 alkyl, or wherein Z ¹ and Z ² or Z ¹ and Z ³ are combined to form -L-, wherein L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -or-C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, wherein at least one group of Z ¹ and Z ² or Z ¹ and Z ³ are combined to form -L-;

Z ⁴ is a bond, -CH ₂ - or -CH ₂ CH ₂ -;

Y ¹ and Y ² are each independently hydrogen, C _1-3 alkyl or C _1-3 haloalkyl;

R is phenyl substituted with ^one to three halogens; and

Each R ^a is independently hydrogen, halogen, hydroxy, or C _1-4 alkyl.

In another embodiment, there is provided a compound having the following formula (II-A):

In another embodiment, there is provided a compound having the following formula (II-B):

In another embodiment, there is provided a compound having the following formula (II-C):

In another embodiment, L is -C(R ^a ) ₂ -. In a further embodiment, L is -C(R ^a ) ₂ C(R ^a ) ₂ -. In yet a further embodiment, L is -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -. In yet a further embodiment, each R ^a is hydrogen. In yet a further embodiment, one R ^a is methyl and each remaining R ^a is hydrogen. In yet a further embodiment, one R ^a is halogen and each remaining R ^a is hydrogen. In yet a further embodiment, two R ^a are halogen and each remaining R ^a is hydrogen. In yet a further embodiment, one R ^a is halogen and each remaining R ^a is hydrogen.

In another embodiment, X is -O-. In another embodiment, X is ^-NZ3- . In another embodiment, X is -NH-. ^In another embodiment, X is ^-CHZ3- and Z1 and Z3 are taken together to form ^-L- . In a further embodiment, Z2 is ^hydrogen . In another embodiment, X is _-CH2- .

In another embodiment, ^Z4 is a bond or _-CH2- . In another embodiment, ^Z4 is _-CH2- . In another embodiment, ^Z4 is a bond.

In another embodiment, ^Y1 and ^Y2 are each independently hydrogen, methyl or trifluoromethyl.

In another embodiment, R ¹ is substituted with one halo. In a further embodiment, R ¹ is 4-fluorophenyl or 2-fluorophenyl.

^In another embodiment, R1 is substituted with two halogens. In ^a further embodiment, R is 2,4-difluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 3-fluoro-4-chlorophenyl, 3, 4-difluorophenyl, 2-fluoro-4-chlorophenyl, or 3,5-difluorophenyl. In yet a further embodiment, R ¹ is 2,4-difluorophenyl.

In another embodiment, R ¹ is substituted with three halogens. In a further embodiment, R ¹ is 2,4,6-trifluorophenyl or 2,3,4-trifluorophenyl. In yet a further embodiment, R ¹ is 2,4,6-trifluorophenyl.

In one embodiment, there is provided a pharmaceutical composition comprising any one of the compounds of formula (I), (II-A), (II-B) or (II-C) as described above or a stereoisomer thereof or may be Pharmaceutically acceptable salts and pharmaceutically acceptable carriers, diluents or excipients.

Another embodiment is provided, comprising administering to humans a therapeutically effective amount of any one compound of formula (I), (II-A), (II-B) or (II-C) as described above or a pharmaceutical combination thereof A method of treating HIV infection in a patient having the infection or at risk of having the infection. Another embodiment is provided, comprising administering to humans a therapeutically effective amount of any one compound of formula (I), (II-A), (II-B) or (II-C) as described above or a pharmaceutical combination thereof A method of treating or preventing HIV infection in a patient having or at risk of having the infection.

In another embodiment, there is provided any compound of formula (I), (II-A), (II-B) or (II-C) as described above or a pharmaceutical composition thereof for the treatment of suffering from an infection or in Use for HIV infection in patients at risk of infection. In another embodiment, there is provided any compound of formula (I), (II-A), (II-B) or (II-C) as described above or a pharmaceutical composition thereof for treating or preventing infection or the use of HIV infection in a patient at risk of having the infection. In another embodiment, there is provided the use of any compound of formula (I), (II-A), (II-B) or (II-C) above or a pharmaceutical composition thereof in medical treatment.

In another embodiment, any compound or pharmaceutical composition thereof in formula (I), (II-A), (II-B) or (II-C) as described above is provided for the therapeutic treatment of HIV infection use. In another embodiment, there is provided any compound of formula (I), (II-A), (II-B) or (II-C) as described above or a pharmaceutical composition thereof for preventive or therapeutic treatment Use for HIV infection.

As further described above, in one embodiment of the present invention there is provided a compound having antiviral activity, said compound having the following formula (I):

or its stereoisomer or pharmaceutically acceptable salt,

in:

X is -O- or -NZ ³ - or -CHZ ³ -;

W is -O- or -NZ ² - or -CHZ ² -;

Z ¹ , Z ² and Z ³ are each independently hydrogen, C _1-3 alkyl or C _1-3 haloalkyl, or wherein Z ¹ and Z ² or Z ¹ and Z ³ are combined to form -L-, wherein L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C( R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C( R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C (R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ OC(R ^a ) ₂ -, - C(R ^a ) ₂ NR ^a C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C( R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ NR ^a C(R ^a ) ₂ -or-C(R ^a ) ₂ NR ^a SO ₂ C(R ^a ) ₂ -;

Z ⁴ is a bond or -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ OCH ₂ -, -CH ₂ NR ^a CH ₂ -, -CH ₂ SCH ₂ -,- CH ₂ S(O)CH ₂ -or -CH ₂ SO ₂ CH ₂ -;

Y and Y are each independently ^hydrogen or C ^1-3 alkyl, or Y and Y together with the carbon atoms to which they are attached form ^a carbocyclic ring having ₃ to 6 ring atoms or have ³ to 6 ring atoms The heterocyclic ring of wherein said carbocyclic or heterocyclic ring is optionally substituted by one or more R ^a ;

R is optionally substituted aryl or optionally substituted heteroaryl ^; and

each R is independently hydrogen, halogen, hydroxy, ^or _C1-4 alkyl, or wherein two R groups together with the carbon atoms to which they are attached form ⁼ O, and

wherein at least ^one of the following: (i) Z1 and Z2 or Z1 and Z3 together form -L-; or (ii) ^Y1 and ^Y2 together with the carbon atoms to which they are attached form ^a ring having ³ to ⁶ rings atoms or heterocyclic rings having 3 to 6 ring atoms.

In another embodiment, W is ^-CHZ2- .

^In another embodiment, Z1 and ^Z2 or ^Z1 and ^Z3 together form -L-.

In another embodiment, there is provided a compound having one of the following formulas (II-A), (II-B) or (II-C):

Where L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C (R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C (R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C (R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ NR ^a C(R ^a ) ₂ - or -C(R ^a ) ₂ NR ^a SO ₂ C(R ^a ) ₂ -.

In another embodiment, ^Y1 and ^Y2 together with the carbon atoms to which they are attached form a carbocyclic ring having 3 to 6 ring atoms or a heterocyclic ring having 3 to 6 ring atoms.

In another embodiment, there is provided a compound having one of the following formulas (III-A), (III-B), (III-C) or (III-D):

Wherein Z ¹ and Z ³ are each independently hydrogen or C _1-3 alkyl.

In another embodiment, there is provided a compound having one of the following formulas (III-E), (III-F), (III-G) or (III-H):

Wherein Z ¹ and Z ³ are each independently hydrogen or C _1-3 alkyl.

In another embodiment, (i) Z ¹ and Z ² or Z ¹ and Z ³ together form -L-, and (ii) Y ¹ and Y ² together with the carbon atoms to which they are attached form a ring having 3 to 6 rings atoms or heterocyclic rings having 3 to 6 ring atoms.

In another embodiment, there is provided a formula (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV- AG) or one of (IV-AH):

Where L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C (R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C (R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C (R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ NR ^a C(R ^a ) ₂ - or -C(R ^a ) ₂ NR ^a SO ₂ C(R ^a ) ₂ -.

In another embodiment, there is provided formula (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV- Compounds of one of BG) or (IV-BH):

Where L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C (R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C (R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C (R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ NR ^a C(R ^a ) ₂ - or -C(R ^a ) ₂ NR ^a SO ₂ C(R ^a ) ₂ -.

In another embodiment, L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -or-C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -. In a further embodiment, L is -C(R ^a ) ₂ -. In yet a further embodiment, L is -C(R ^a ) ₂ C(R ^a ) ₂ -. In yet a further embodiment, L is -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -. In yet a further embodiment, each R ^a is hydrogen. In yet a further embodiment, one R ^a is methyl and each remaining R ^a is hydrogen. In yet a further embodiment, one R ^a is halogen and each remaining R ^a is hydrogen. In yet a further embodiment, two R ^a are halogen and each remaining R ^a is hydrogen. In yet a further embodiment, one R ^a is halogen and each remaining R ^a is hydrogen.

In another embodiment, L is -C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC( R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, or -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -. In a further embodiment, L is -C(R ^a ) ₂ OC(R ^a ) ₂ -. In yet a further embodiment, each R ^a is hydrogen. In yet a further embodiment, one R ^a is methyl and each remaining R ^a is hydrogen. In yet a further embodiment, one R ^a is halogen and each remaining R ^a is hydrogen. In yet a further embodiment, two R ^a are halogen and each remaining R ^a is hydrogen. In yet a further embodiment, one R ^a is halogen and each remaining R ^a is hydrogen.

In another embodiment, X is -O-. In a further embodiment, Z2 is ^hydrogen . In another embodiment, X is ^-NZ3- . In another embodiment, X is -NH-. In another embodiment, X is ^-CHZ3- . In another embodiment, X is _-CH2- .

In another embodiment, ^Z4 is a bond or _-CH2- . In another embodiment, ^Z4 is _-CH2- . In another embodiment, ^Z4 is a bond.

In another embodiment, ^Y1 and ^Y2 are each independently hydrogen, methyl or trifluoromethyl.

In another embodiment, R ¹ is substituted with one halo. In a further embodiment, R ¹ is 4-fluorophenyl or 2-fluorophenyl.

^In another embodiment, R1 is phenyl. In another embodiment, R ¹ is pyridyl.

In another embodiment, R ¹ is substituted with at least one halogen.

In another embodiment, R ¹ is substituted with one halo. In a further embodiment, R ¹ is 4-fluorophenyl or 2-fluorophenyl.

^In another embodiment, R1 is substituted with two halogens. In ^a further embodiment, R is 2,4-difluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 3-fluoro-4-chlorophenyl, 3, 4-difluorophenyl, 2-fluoro-4-chlorophenyl, or 3,5-difluorophenyl. In yet a further embodiment, R ¹ is 2,4-difluorophenyl.

In another embodiment, R ¹ is substituted with three halogens. In a further embodiment, R ¹ is 2,4,6-trifluorophenyl or 2,3,4-trifluorophenyl. In yet a further embodiment, R ¹ is 2,4,6-trifluorophenyl.

In another embodiment, R1 is ³ -trifluoromethyl-4-fluorophenyl or 2-cyclopropyl-4-fluorophenyl.

In one embodiment, there is provided a pharmaceutical composition comprising formula (I), (II-A), (II-B), (II-C), (III-A), (III-B) as described above , (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), ( IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV- A compound of any one of BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG) and (IV-BH), or a stereoisomer or a pharmaceutically acceptable salt thereof, And pharmaceutically acceptable carrier, diluent or excipient.

Another embodiment is provided, which comprises formula (I), (II-A), (II-B), (II-C), (III-A), ( III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV- AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB) , (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG), and (IV-BH) any compound or pharmaceutical composition thereof to treat patients A method of HIV infection in a person infected or at risk of having the infection. Another embodiment is provided, which comprises formula (I), (II-A), (II-B), (II-C), (III-A), ( III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV- AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB) , (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG) and (IV-BH) any one of the compound or pharmaceutical composition thereof to treat or prevent A method of HIV infection in a human having the infection or at risk of having the infection.

In another embodiment, there is provided formula (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C) as described above ), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV - a compound of any one of BD), (IV-BE), (IV-BF), (IV-BG) and (IV-BH) or a pharmaceutical composition thereof for the treatment of having an infection or being at risk of having an infection Use in people with HIV infection. In another embodiment, there is provided formula (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C) as described above ), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV - BD), (IV-BE), (IV-BF), (IV-BG), and (IV-BH) any one of the compound or pharmaceutical composition thereof for the treatment or prevention of infection or in patients with HIV-infected use in persons at risk of infection.

In another embodiment, there is provided any one of formula (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III- C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC) , (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), ( IV-BD), (IV-BE), (IV-BF), (IV-BG) and (IV-BH) or pharmaceutical compositions thereof in medical treatment.

In another embodiment, there is provided any one of formula (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III- C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC) , (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), ( IV-BD), (IV-BE), (IV-BF), (IV-BG) and (IV-BH) any one of the compound or pharmaceutical composition thereof for the therapeutic treatment of HIV infection. In another embodiment, there is provided any one of formula (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III- C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC) , (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), ( IV-BD), (IV-BE), (IV-BF), (IV-BG) and (IV-BH) or pharmaceutical compositions thereof for the prophylactic or therapeutic treatment of HIV infection.

It should be understood that, as mentioned above, formulas (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III- D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD) , (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), ( Any embodiment of the compound of IV-BE), (IV-BF), (IV-BG) and (IV-BH), and herein for formula (I), (II-A), (II-B ), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV -AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG) and (IV-BH ) in the compound of R ¹ , R ^a , X, W, Y ¹ , Y ² , L, Z ¹ , Z ² , Z ³ or Z ⁴ groups described in any specific substituent may be independently combined with other embodiments and/or formula (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV -AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE ), (IV-BF), (IV-BG) and (IV-BH) are combined to form embodiments of the invention not specifically described above. In addition, substitutions listed for any particular R ¹ , R ^a , X, W, Y ¹ , Y ² , L, Z ¹ , Z ² , Z ³ or Z ⁴ in particular embodiments and/or claims In the case of a list of substituents, it is understood that each individual substituent may be deleted from a particular embodiment and/or claim and the remaining list of substituents is considered within the scope of the invention.

As will be understood by those skilled in the art, formula (I), (II-A), (II-B), (II-C), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV -BD), (IV-BE), (IV-BF), (IV-BG) and (IV-BH) compounds, wherein Z ¹ and Z ² or Z ¹ and Z ³ together form -L-, can be Displayed in several different ways. For example, compound 3 of Example 3 can be shown as:

pharmaceutical composition

For administration purposes, in some embodiments, the compounds described herein are administered as raw chemicals or formulated as pharmaceutical compositions. The pharmaceutical compositions disclosed herein include a compound of formula (I) and one or more of the following: pharmaceutically acceptable carriers, diluents or excipients. The compound of formula (I) is present in the composition in an amount effective to treat the particular disease or condition of interest. The activity of compounds of formula (I) can be determined by a person skilled in the art, for example as described below. Appropriate concentrations and dosages can be readily determined by those skilled in the art. In some embodiments, the compound of formula (I) is present in the pharmaceutical composition in an amount from about 25 mg to about 500 mg. In some embodiments, the compound of formula (I) is present in the pharmaceutical composition in an amount from about 100 mg to about 300 mg. In some embodiments, the compound of formula (I) is present in the pharmaceutical composition in an amount of about 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or about 500 mg.

Administration of a compound of the invention, or a pharmaceutically acceptable salt thereof, in pure form or in a suitable pharmaceutical composition is by any of the modes of administration acceptable for use as an agent for similar purposes. The pharmaceutical compositions of the present invention are prepared by mixing a compound of the present invention with a suitable pharmaceutically acceptable carrier, diluent or excipient and, in certain embodiments, formulated in solid, semi-solid, liquid or gaseous form formulations, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols. Exemplary routes of administration of such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal and intranasal. Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions to be administered to a subject or patient take the form of one or more dosage units, where, for example, a tablet can be a single dosage unit and a container of a compound of the invention in aerosol form can hold multiple dosage units . Actual methods of preparing such dosage forms are known, or will be apparent to those skilled in the art, see, eg, Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). In any event, the compositions to be administered contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the treatment of a disease or condition of interest in light of the teachings described herein.

The pharmaceutical compositions disclosed herein are prepared by methods well known in the art of pharmacy. For example, in some embodiments, pharmaceutical compositions intended for administration by injection are prepared by mixing a compound of the invention with sterile distilled water so as to form a solution. In certain embodiments, surfactants are added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that interact non-covalently with the compounds of the invention to facilitate dissolution or uniform suspension of the compounds in aqueous delivery systems.

A compound of the invention, or a pharmaceutically acceptable salt thereof, is administered in a therapeutically effective amount that will vary depending on a number of factors, including the activity of the particular compound employed; the metabolic stability and length of action of the compound; the age of the patient. , body weight, general health status, sex, and diet; mode and timing of administration; rate of excretion; drug combination; severity of the specific disorder or condition; and ongoing treatment of the subject.

combination therapy

In one embodiment, there is provided a method for treating or preventing HIV infection in a human having or at risk of having the infection, comprising administering to said human a therapeutically effective amount of a compound disclosed herein, or A pharmaceutically acceptable salt in combination with a therapeutically effective amount of one or more additional therapeutic agents.

In one embodiment, there is provided a pharmaceutical composition comprising a compound disclosed herein, a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent or excipient.

In one embodiment, there is provided a pharmaceutical agent comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents.

In the above embodiments, the additional therapeutic agent may be an anti-HIV agent. For example, in certain embodiments, the additional therapeutic agent is selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase , HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, entry inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (ie fusion inhibitors) and CD4 linkage inhibitors), CXCR4 Inhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors, compounds targeting the HIV capsid ("capsid inhibitors"; for example capsid polymerization inhibitors or capsid disrupting compounds such as in WO 2013/006738 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania) and WO 2013/006792 (Pharma Resources), pharmacokinetic enhancers, and other drugs for the treatment of HIV, and combinations thereof. In a further embodiment, the additional therapeutic agent is selected from one or more of the following;

(1) HIV protease inhibitors, selected from amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, Tipranavir, Brinavir, Darunavir, TMC-126, TMC-114, Mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI -272, DPC-681, DPC-684, GW640385X, DG17, PPL-100, DG35 and AG 1859;

(2) HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, selected from capravirine, emivirine (emivirine), delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine , GW5634, DPC-083, DPC-961, DPC-963, MIV-150, TMC-120, rilpivirene, BILR 355BS, VRX 840773, lesvirin (UK-453061), RDEA806, KM023 and MK-1439;

(3) HIV nucleoside inhibitors of reverse transcriptase, selected from zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, Amdosovir, Eftabine, Alovudine, MIV-210, ±-FTC, D-d4FC, Emtricitabine, Phosphine Azide, Fozivudine tidoxil, Apricitibine, ( AVX754), KP-1461, GS-9131 (Gilead Sciences) and fosalvudine tidoxil (formerly HDP 99.0003);

(4) HIV nucleotide inhibitors of reverse transcriptase, selected from tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate (Gilead Sciences), GS-7340 (Gilead Sciences), GS-9148 (Gilead Sciences), adefovir, adefovir dipivoxil, CMX-001 (Chimerix), or CMX-157 (Chimerix);

(5) HIV integrase inhibitor, selected from curcumin, derivatives of curcumin, cichoric acid, derivatives of cichoric acid, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid Derivatives of aurintricarboxylic acid, derivatives of aurintricarboxylic acid, phenethyl caffeate, derivatives of phenethyl caffeate, tyrphostin, tyrosine Derivatives of phosphorylation inhibitors, quercetin, derivatives of quercetin, S-1360, AR-177, L-870812, and L-870810, raltegravir, BMS-538158, GSK364735C, BMS-707035, MK-2048, BA 011, elvitegravir, dolutegravir and GSK-744;

(6) HIV non-catalytic sites or allosteric integrase inhibitors (NCINI), including but not limited to: BI-224436, CX0516, CX05045, CX14442, in WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 ( Boehringer Ingelheim), WO2013/159064 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO2012/003497 (Gilead Sciences), WO 2012/003498 (Gilead Sciences), the entire contents of each of which are incorporated incorporated herein by reference;

(7) gp41 inhibitors, selected from enfuvirtide, sifuvirtide, albuvirtide, FB006M and TRI-1144;

(8) CXCR4 inhibitor AMD-070;

(9) entry inhibitor SP01A;

(10) gp120 inhibitor BMS-488043;

(11) G6PD and NADH-oxidase inhibitor immunin;

(12) CCR5 inhibitor selected from the group consisting of alaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, INCB15050, PF-232798 (Pfizer) and CCR5mAb004;

(13) CD4 linkage inhibitor, selected from ibalizumab (TMB-355) and BMS-068 (BMS-663068);

(14) A pharmacokinetic enhancer selected from cobicistat and SPI-452; and

(15) Other drugs for treating HIV, selected from: BAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1, PA-457 (bevirimat), HRG214, VGX-410, KD-247, AMZ 0026, CYT99007A-221HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889 and PA-1050040 (PA-040),

and combinations thereof.

In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two, three, four or more additional therapeutic agents. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In a further embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The two, three, four or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, or they may be selected from different classes of therapeutic agents. In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleotide inhibitor of reverse transcriptase and an HIV protease inhibitory compound of reverse transcriptase. In a further embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with HIV nucleotide inhibitors of reverse transcriptase, HIV non-nucleoside inhibitors of reverse transcriptase, and HIV protease inhibitory compounds. In an additional embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer.

In some embodiments, when a compound disclosed herein is combined with one or more additional therapeutic agents as described above, the components of the composition are administered in a simultaneous or sequential schedule. When administered sequentially, the combination may be administered in two or more doses.

In some embodiments, a compound disclosed herein is combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a patient, eg, in a solid dosage form for oral administration.

In some embodiments, a compound disclosed herein is administered with one or more additional therapeutic agents. Co-administration of a compound disclosed herein and one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents such that a therapeutically effective amount of a compound disclosed herein and one or more additional therapeutic agents are administered. One or more additional therapeutic agents are present in the patient at the same time.

Co-administration includes administering a unit dose of a compound disclosed herein either before or after administration of a unit dose of one or more additional therapeutic agents, e.g., in conjunction with administration of one or more additional therapeutic agents The compounds disclosed herein are administered within seconds, minutes or hours. For example, in certain embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein within seconds or minutes. In certain embodiments, a unit dose of a compound disclosed herein is administered first followed by administration of a unit dose of one or more additional therapeutic agents over a period of hours (eg, 1-12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of a compound disclosed herein over a period of hours (eg, 1-12 hours).

The following examples illustrate the preparation of compounds of the invention (ie, compounds of formula (I):

wherein R ¹ , X, W, Y ¹ , Y ² , Z ¹ , Z ² or Z ⁴ are as defined above. Those skilled in the art will understand that these compounds may be able to be prepared by similar methods or by combining other methods known to those skilled in the art. Those skilled in the art will also understand that other compounds of formula (I) not explicitly described below can be prepared in a similar manner as described below, by using suitable starting components and adjusting synthesis parameters as required. Typically, starting components can be obtained from sources such as SigmaAldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc., or synthesized according to sources known to those skilled in the art (see, e.g., Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or prepared as described herein.

For purposes of illustration only, the present invention includes but not limited to the following technical solutions:

Technical scheme 1. has the compound of following formula (I):

or its stereoisomer or pharmaceutically acceptable salt,

in:

X is -O- or -NZ ³ - or -CHZ ³ -;

W is -CHZ ² -;

Z ¹ , Z ² and Z ³ are each independently hydrogen or C _1-3 alkyl, or wherein Z ¹ and Z ² or Z ¹ and Z ³ are combined to form -L-, wherein L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, or -C(R ^a ) ₂ C( R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, wherein at least one group of Z ¹ and Z ² or Z ¹ and Z ³ together form -L-;

Z ⁴ is a bond, -CH ₂ - or -CH ₂ CH ₂ -;

Y ¹ and Y ² are each independently hydrogen, C _1-3 alkyl or C _1-3 haloalkyl;

R is phenyl substituted with ^one to three halogens; and

Each R ^a is independently hydrogen, halogen, hydroxy, or C _1-4 alkyl.

Technical scheme 2. the compound of technical scheme 1, has following formula (II-A):

Technical scheme 3. the compound of technical scheme 1, has following formula (II-B):

Technical scheme 4. The compound of technical scheme 1, has following formula (II-c):

Technical scheme 5. The compound according to any one of technical schemes 1-4, wherein L is -C(R ^a ) ₂ -.

Technical scheme 6. The compound according to any one of technical schemes 1-4, wherein L is -C(R ^a ) ₂ C(R ^a ) ₂ -.

Technical scheme 7. The compound according to any one of technical schemes 1-4, wherein L is -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -.

Technical scheme 8. The compound according to any one of technical schemes 1-7, wherein each R ^a is hydrogen.

Technical scheme 9. The compound according to any one of technical schemes 1-7, wherein one R ^a is methyl and each of the remaining R ^a is hydrogen.

Technical scheme 10. The compound according to any one of technical schemes 1-7, wherein at least one R ^a is halogen and each of the remaining R ^a is hydrogen.

Technical scheme 11. The compound according to any one of technical schemes 1-7, wherein two R ^a are halogen and each remaining R ^a is hydrogen.

Technical scheme 12. The compound according to any one of technical schemes 1-7, wherein one R ^a is halogen and each of the remaining R ^a is hydrogen.

Technical scheme 13. The compound according to any one of technical schemes 1-2 or 5-12, wherein X is -O-.

Technical scheme 14. The compound according to any one of technical schemes 1-2 or 5-12, wherein X is -NZ ³ -.

Technical scheme 15. The compound according to any one of technical schemes 1-2 or 5-12, wherein X is -NH-.

Technical scheme 16. The compound according to any one of technical schemes 1-2 or 5-12, wherein X is -CHZ ³ - and Z ¹ and Z ³ together form -L-.

Technical scheme 17. The compound of technical scheme 16, wherein Z ² is hydrogen.

Technical scheme 18. The compound according to any one of technical schemes 1-2 or 5-12, wherein X is -CH ₂ -.

Technical scheme 19. The compound according to any one of technical scheme 1 or 5-18, wherein Z ⁴ is a bond or -CH ₂ -.

Technical scheme 20. The compound according to any one of technical scheme 1 or 5-18, wherein Z ⁴ is -CH ₂ -.

Technical scheme 21. The compound according to any one of technical scheme 1 or 5-18, wherein Z ⁴ is a bond.

Technical scheme 22. The compound according to any one of technical scheme 1 or 5-21, wherein Y ¹ and Y ² are each independently hydrogen, methyl or trifluoromethyl.

Technical scheme 23. The compound according to any one of technical schemes 1-22, wherein R ¹ is substituted by a halogen.

Technical scheme 24. The compound of technical scheme 23, wherein R ¹ is 4-fluorophenyl or 2-fluorophenyl.

Technical scheme 25. The compound according to any one of technical schemes 1-22, wherein R ¹ is substituted by two halogens.

Technical scheme 26. The compound of technical scheme 25, wherein R is 2,4 ^- difluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 3-fluoro-4-chlorophenyl , 3,4-difluorophenyl, 2-fluoro-4-chlorophenyl, or 3,5-difluorophenyl.

Technical scheme 27. The compound of technical scheme 26, wherein R ¹ is 2,4-difluorophenyl.

Technical scheme 28. The compound according to any one of technical schemes 1-22, wherein R ¹ is substituted by three halogens.

Technical scheme 29. The compound of technical scheme 28, wherein R ¹ is 2,4,6-trifluorophenyl or 2,3,4-trifluorophenyl.

Technical scheme 30. The compound of technical scheme 29, wherein R ¹ is 2,4,6-trifluorophenyl.

Technical scheme 31. The compound of technical scheme 1, selected from:

Technical scheme 32. The compound of technical scheme 1, selected from:

Technical scheme 33. A pharmaceutical composition, comprising the compound of any one of technical schemes 1-32 or its stereoisomer or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, diluent or excipient.

Technical scheme 34. The pharmaceutical composition of technical scheme 33, further comprising one or more additional therapeutic agents.

Technical scheme 35. The pharmaceutical composition of technical scheme 34, wherein the one or more additional therapeutic agents are anti-HIV agents.

Technical scheme 36. The pharmaceutical composition of technical scheme 35, wherein said one or more additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase , HIV nucleotide inhibitors of reverse transcriptase, and combinations thereof.

Technical scheme 37. A method for treating HIV infection in a person suffering from infection or at risk of having infection, by administering to said human a therapeutically effective amount of the compound of any one of technical schemes 1-32 or The pharmaceutical composition of technical scheme 33.

Technical solution 38. The method of technical solution 37, further comprising administering a therapeutically effective amount of one or more additional therapeutic agents to the human.

Technical scheme 39. The method of technical scheme 38, wherein the one or more additional therapeutic agents are anti-HIV agents.

Technical scheme 40. The method of technical scheme 39, wherein said one or more additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, reverse HIV nucleotide inhibitors of logase, and combinations thereof.

Technical scheme 41. Use of the compound of any one of technical schemes 1-32 or the pharmaceutical composition of technical scheme 33 for treating HIV infection in a human suffering from infection or at risk of suffering from infection.

Technical solution 42. The use of technical solution 41, further comprising administering a therapeutically effective amount of one or more additional therapeutic agents to the human.

Technical scheme 43. The use of technical scheme 42, wherein the one or more additional therapeutic agents are anti-HIV agents.

Technical scheme 44. the purposes of technical scheme 43, wherein said one or more other therapeutic agents are selected from the HIV protease inhibitor, the HIV non-nucleoside inhibitor of reverse transcriptase, the HIV nucleoside inhibitor of reverse transcriptase, reverse HIV nucleotide inhibitors of logase, and combinations thereof.

Technical scheme 45. The compound according to any one of technical schemes 1-32 or a pharmaceutically acceptable salt thereof, for use in medical treatment.

Technical scheme 46. The compound according to any one of technical schemes 1-32 or a pharmaceutically acceptable salt thereof, for therapeutic treatment of HIV infection.

Technical scheme 47. has the compound of following formula (I):

or its stereoisomer or pharmaceutically acceptable salt,

in:

X is -O- or -NZ ³ - or -CHZ ³ -;

W is -O- or -NZ ² - or -CHZ ² -;

Z ¹ , Z ² and Z ³ are each independently hydrogen or C _1-3 alkyl, or wherein Z ¹ and Z ² or Z ¹ and Z ³ are combined to form -L-, wherein L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, - C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ NR ^a C(R ^a ) ₂ -or -C(R ^a ) ₂ NR ^a SO ₂ C(R ^a ) ₂ −;

Z ⁴ is a bond or -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ OCH ₂ -, -CH ₂ NR ^a CH ₂ -, -CH ₂ SCH ₂ -, - CH ₂ S(O)CH ₂ -or -CH ₂ SO ₂ CH ₂ -;

Y and Y are each independently ^hydrogen , C ^1-3 alkyl or C _1-3 haloalkyl, or Y and Y together with the carbon atoms to which they are attached form ^a carbocyclic ring having ₃ to ⁶ ring atoms, or ^a heterocyclic ring having 3 to 6 ring atoms, wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more R;

R is optionally substituted aryl or optionally substituted heteroaryl ^; and

each R is independently hydrogen, halogen, hydroxy, ^or _C1-4 alkyl, or wherein two R groups together with the carbon atoms to which they are attached form C ⁼ O, and

wherein at least one of: (i) Z ¹ and Z ² or Z ¹ and Z ³ together form -L-; or (ii) Y ¹ and Y ² together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic rings having 3 to 6 ring atoms.

Technical scheme 48. The compound of technical scheme 47, wherein W is -CHZ ² -.

Technical scheme 49. The compound of technical scheme 47 or 48, wherein Z ¹ and Z ² or Z ¹ and Z ³ together form -L-.

Technical scheme 50. The compound of technical scheme 49, having one of the following formulas (II-A), (II-B) or (II-C):

Where L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C (R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C (R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C (R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ NR ^a C(R ^a ) ₂ - or -C(R ^a ) ₂ NR ^a SO ₂ C(R ^a ) ₂ -.

Technical scheme 51. The compound of technical scheme 47 or 48, wherein Y ¹ and Y ² together with the carbon atoms to which they are attached form a carbocyclic ring having 3 to 6 ring atoms or a heterocyclic ring having 3 to 6 ring atoms.

Technical scheme 52. The compound of technical scheme 51, having one of the following formulas (III-A), (III-B), (III-C) or (III-D):

Wherein Z ¹ and Z ³ are each independently hydrogen or C _1-3 alkyl.

Technical scheme 53. The compound of technical scheme 51, having one of the following formulas (III-E), (III-F), (III-G) or (III-H):

Wherein Z ¹ and Z ³ are each independently hydrogen or C _1-3 alkyl.

Technical scheme 54. The compound of technical scheme 47 or 48, wherein (i) Z ¹ and Z ² or Z ¹ and Z ³ together form -L-, and (ii) Y ¹ and Y ² form together with the carbon atom that they connect A carbocyclic ring having 3 to 6 ring atoms or a heterocyclic ring having 3 to 6 ring atoms.

Technical scheme 55. The compound of technical scheme 54 has one of the following formulas: (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF ), (IV-AG) or (IV-AH):

Where L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C (R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C (R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C (R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ NR ^a C(R ^a ) ₂ - or -C(R ^a ) ₂ NR ^a SO ₂ C(R ^a ) ₂ -.

Technical scheme 56. The compound of technical scheme 54, has one of following formula: (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF ), (IV-BG) or (IV-BH):

Where L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C (R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C (R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ OC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C (R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ S(O)C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ SO ₂ C(R ^a ) ₂ -, -C(R ^a ) ₂ SO ₂ NR ^a C(R ^a ) ₂ - or -C(R ^a ) ₂ NR ^a SO ₂ C(R ^a ) ₂ -.

Technical scheme 57. The compound according to any one of technical schemes 47-50 or 54-56, wherein L is -C(R ^a ) ₂ -, -C(R ^a ) ₂ C(R ^a ) ₂ -, -C( R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ - or -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -.

Technical scheme 58. The compound of technical scheme 57, wherein L is -C(R ^a ) ₂ -.

Technical scheme 59. The compound of technical scheme 57, wherein L is -C(R ^a ) ₂ C(R ^a ) ₂ -.

Technical scheme 60. The compound of technical scheme 57, wherein L is -C(R ^a ) ₂ C(R ^a ) ₂ C(R ^a ) ₂ -.

Technical scheme 61. The compound according to any one of technical schemes 47-50 or 54-60, wherein each R ^a is hydrogen.

Technical scheme 62. The compound according to any one of technical schemes 47-50 or 54-60, wherein one R ^a is methyl and each of the remaining R ^a is hydrogen.

Technical scheme 63. The compound according to any one of technical schemes 47-50 or 54-60, wherein at least one R ^a is halogen and each of the remaining R ^a is hydrogen.

Technical scheme 64. The compound according to any one of technical schemes 47-50 or 54-60, wherein two R ^a are halogen and each remaining R ^a is hydrogen.

Technical scheme 65. The compound according to any one of technical schemes 47-50 or 54-60, wherein one R ^a is halogen and each of the remaining R ^a is hydrogen.

Technical scheme 66. The compound according to any one of technical schemes 47-50 or 54-56, wherein L is -C(R ^a ) ₂ OC(R ^a ) ₂ -, -C(R ^a ) ₂ NR ^a C(R ^a ) ₂ -, -C(R ^a ) ₂ SC(R ^a ) ₂ -, -C(R ^a ) ₂ S(O)C(R ^a ) ₂ -or -C(R ^a ) ₂ SO ₂ C( R ^a ) ₂ -.

Technical scheme 67. The compound according to any one of technical schemes 47-50 or 54-56, wherein L is -C(R ^a ) ₂ OC(R ^a ) ₂ -.

Technical scheme 68. The compound of technical scheme 66 or 67, wherein each R ^a is hydrogen.

Technical scheme 69. The compound of technical scheme 66 or 67, wherein one R ^a is methyl and each of the remaining R ^a is hydrogen.

Technical scheme 70. The compound of technical scheme 66 or 67, wherein at least one R ^a is halogen and each of the remaining R ^a is hydrogen.

Technical scheme 71. The compound of technical scheme 66 or 67, wherein two R ^a are halogen and each remaining R ^a is hydrogen.

Technical scheme 72. The compound of technical scheme 66 or 67, wherein one R ^a is halogen and each of the remaining R ^a is hydrogen.

Technical scheme 73. The compound according to any one of technical schemes 47-55 or 57-72, wherein X is -O-.

Technical scheme 74. The compound of technical scheme 73, wherein Z ² is hydrogen.

Technical scheme 75. The compound according to any one of technical schemes 47-72, wherein X is -NZ ³ -.

Technical scheme 76. The compound according to any one of technical schemes 47-72, wherein X is -NH-.

Technical scheme 77. The compound according to any one of technical schemes 47-55 or 57-72, wherein X is -CHZ ³ -.

Technical scheme 78. The compound according to any one of technical schemes 47-55 or 57-72, wherein X is -CH ₂ -.

Technical scheme 79. The compound according to any one of technical schemes 47-49, 51, 54 or 57-78, wherein Z ⁴ is a bond or -CH ₂ -.

Technical scheme 80. The compound according to any one of technical schemes 47-49, 51, 54 or 57-78, wherein Z ⁴ is -CH ₂ -.

Technical scheme 81. The compound according to any one of technical schemes 47-49, 51, 54 or 57-78, wherein Z ⁴ is a bond.

Technical scheme 82. The compound according to any one of technical schemes 47-49 or 57-81, wherein Y ¹ and Y ² are each independently hydrogen, methyl or trifluoromethyl.

Technical scheme 83. The compound according to any one of technical schemes 47-82, wherein R ¹ is phenyl.

Technical scheme 84. The compound according to any one of technical schemes 47-82, wherein R ¹ is pyridyl.

Technical scheme 85. The compound according to any one of technical schemes 47-84, wherein R ¹ is substituted by at least one halogen.

Technical scheme 86. The compound according to any one of technical schemes 47-84, wherein R ¹ is substituted by a halogen.

Technical scheme 87. The compound of technical scheme 86, wherein R ¹ is 4-fluorophenyl or 2-fluorophenyl.

Technical scheme 88. The compound according to any one of technical schemes 47-84, wherein R ¹ is substituted by two halogens.

Technical scheme 89. The compound of technical scheme 88, wherein R is 2,4 ^- difluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 3-fluoro-4-chlorophenyl , 3,4-difluorophenyl, 2-fluoro-4-chlorophenyl, or 3,5-difluorophenyl.

Technical scheme 90. The compound of technical scheme 89, wherein R ¹ is 2,4-difluorophenyl.

Technical scheme 91. The compound according to any one of technical schemes 47-84, wherein R ¹ is substituted by three halogens.

Technical scheme 92. The compound of technical scheme 91, wherein R ¹ is 2,4,6-trifluorophenyl or 2,3,4-trifluorophenyl.

Technical scheme 93. The compound of technical scheme 92, wherein R ¹ is 2,4,6-trifluorophenyl.

Technical scheme 94. The compound of technical scheme 85, wherein R ¹ is 3-trifluoromethyl-4-fluorophenyl or 2-cyclopropoxy-4-fluorophenyl.

Technical scheme 95. A pharmaceutical composition, comprising the compound of any one of technical schemes 47-94 or its stereoisomer or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, diluent or excipient.

Technical scheme 96. The pharmaceutical composition of technical scheme 95, further comprising one or more additional therapeutic agents.

Technical scheme 97. The pharmaceutical composition of technical scheme 96, wherein the one or more additional therapeutic agents are anti-HIV agents.

Technical scheme 98. The pharmaceutical composition of technical scheme 97, wherein said one or more additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase , HIV nucleotide inhibitors of reverse transcriptase, and combinations thereof.

Technical scheme 99. A method for treating HIV infection in a person suffering from infection or at risk of having infection, by administering to said human a therapeutically effective amount of the compound of any one of technical schemes 47-94 or The pharmaceutical composition of technical scheme 95.

Technical solution 100. The method of technical solution 99, further comprising administering to the human a therapeutically effective amount of one or more additional therapeutic agents.

Technical scheme 101. The method of technical scheme 100, wherein the one or more additional therapeutic agents are anti-HIV agents.

Technical scheme 102. The method of technical scheme 101, wherein said one or more additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, reverse HIV nucleotide inhibitors of logase, and other drugs for the treatment of HIV, and combinations thereof.

Technical scheme 103. Use of the compound of any one of technical schemes 47-94 or the pharmaceutical composition of technical scheme 95 for treating HIV infection in a human suffering from infection or at risk of suffering from infection.

Technical solution 104. The use of technical solution 103, further comprising administering a therapeutically effective amount of one or more additional therapeutic agents to the human.

Technical scheme 105. The use of technical scheme 104, wherein the one or more additional therapeutic agents are anti-HIV agents.

Technical scheme 106. the purposes of technical scheme 105, wherein said one or more additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, reverse HIV nucleotide inhibitors of logase, and other drugs for the treatment of HIV, and combinations thereof.

Technical scheme 107. The compound according to any one of technical schemes 47-94 or a pharmaceutically acceptable salt thereof, for medical treatment.

Technical scheme 108. The compound according to any one of technical schemes 47-94 or a pharmaceutically acceptable salt thereof, for therapeutic treatment of HIV infection.

The following examples are offered for purposes of illustration, not limitation.

Example

General Synthetic Scheme

Schemes 1-3 are provided as further embodiments of the present invention and illustrate general methods for the preparation of compounds of formula (I) and which may be used to prepare additional compounds of formula (I).

plan 1

Al can be converted to amide A2 using a suitable amine and coupling reagent such as HATU or EDCI. A2 can be converted to A3 with a strong acid such as methanesulfonic acid. A3 can be converted to A5 or A4 by heating with an appropriate cyclic diamine or cyclic aminoalcohol followed by methyl deprotection with a reagent such as magnesium bromide.

Alternatively, Al can be converted to A6 by treatment with a strong acid such as methanesulfonic acid. A6 can be condensed with a suitable cyclic diamine or cyclic aminoalcohol followed by methyl deprotection with a reagent such as magnesium bromide to form A7 or A8 respectively. A7 or A8 can be converted to amides A5 and A4 by treatment with a suitable amine and coupling reagent such as HATU or EDCI, followed by methyl deprotection with a reagent such as magnesium bromide. Scenario 2

Condensation of B1 (as described in WO2012/018065) with a diamine under reflux conditions affords B2. Hydrolysis of B2 and coupling with the amine via the amide formation method afforded the product when the benzyl protecting group was removed

Object B3.

representative compound

Example 1

Preparation of Compound 1

N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridge Methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

step 1

Will

1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1- A, 0.300 g, 0.95 mmol), prepared as described in WO2011/119566A1, evaporated once from anhydrous toluene, suspended in acetonitrile (4 mL), and washed with N,N-diisopropylethylamine (DIPEA) (0.329 mL , 1.90mmol), 2,4-difluorobenzylamine (0.125mL, 1.05mmol) and HATU (0.433g, 1.14mmol). The reaction mixture was stirred for 10 minutes and concentrated. Purification of the residue by flash chromatography on silica gel (10 to 60% ethyl acetate:dichloromethane) gave the compound 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2 -Dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid methyl ester, 1-B. ¹ H-NMR (400MHz, DMSO-d6) δ10.28(t, J=6.0Hz, 1H), 8.46(s, 1H), 7.42(dd, J=15.4, 8.6Hz, 1H), 7.24(m, 1H), 7.06(m, 1H), 4.52(m, 3H), 4.22(d, J=4.4Hz, 2H), 3.92(s, 3H), 3.80(s, 3H), 3.29(d, 6H). LCMS-ESI ⁺ (m/z): [M ^+H]+ _{calcd for C20H23F2N2O7} : _441.15 ; found: _441.2 .

step 2

5-(2,4-Difluorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-3-methanol in acetonitrile (0.9 mL) and acetic acid (0.1 mL) Oxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid methyl ester (1-B, 0.106 g, 0.24 mmol) was treated with methanesulfonic acid (0.005 mL, 0.072 mmol) and sealed with a yellow cap , and heated to 70°C. After 16 hours, the mixture was cooled to give 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyacetoxy)-3-methoxy-4-oxo A crude solution of methyl 1,4-dihydropyridine-2-carboxylate 1-C. LCMS-ESI ⁺ (m/z): [M ₊ H] ⁺ _calcd for _C18H19F2N2O7 : _413.12 ; found: _413.1 .

Steps 3 and 4

Treat 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)- 3-Methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid methyl ester (1-C, 0.65 mL of crude mixture from previous step 0.17 mmol). The reaction mixture was sealed and heated to 90 °C. After 30 minutes, the reaction mixture was cooled and magnesium bromide (0.063 g, 0.34 mmol) was added. The mixture was resealed and heated to 50 °C. After 10 minutes, the reaction mixture was partitioned between dichloromethane and hydrochloric acid (0.2 Maq). The organic layer was removed, and the aqueous layer was extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Prep-HPLC purification (30-70% acetonitrile:water, 0.1% TFA) afforded compound 1 as a racemic mixture. ¹ H-NMR (400MHz, DMSO-d6) δ12.45(brs, 1H), 10.35(t, J=5.8Hz, 1H), 8.45(s, 1H), 7.37(dd, J=15.4, 8.6Hz, 1H), 7.23(dt, J=2.5, 9.9Hz, 1H), 7.05(dt, J=2.2, 8.7Hz, 1H), 5.43(dd, J=9.6, 4.0Hz, 1H), 5.09(br s, 1H), 4.68(dd, J=13.2, 4.0Hz, 1H), 4.59(br s, 1H), 4.53(m, 2H), 4.02(dd, J=12.6, 9.4Hz), 1.93(br s, 4H ), 1.83 (d, J=12.0Hz), 1.57 (dt, J=12.2, 3.2Hz). LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value for C ₂₁ H ₂₀ F ₂ N ₃ O ₅ : 432.14; found value: 432.2.

Examples 2 and 3

Preparation of Compounds 2 and 3

(2R,5S,13aR)-N-(2,4-Difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a- Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide (2 ) and (2S,5R,13aS)-N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13, 13a-Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide (3)

Compound 1 (16 mg) was separated by chiral HPLC using Chiralpak AS-H with 100% ethanol as eluent to afford compounds 2 and 3 in enantiomerically enriched form. For compound 2: LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value: C ₂₁ H ₂₀ F ₂ N ₃ O ₅ : 432.14; found value: 432.2, chiral HPLC retention time = 4.50 minutes ( Chiralpak AS-H, 150x4.6mm, 1 mL/min EtOH). For compound 3: LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value: C ₂₁ H ₂₀ F ₂ N ₃ O ₅ : 432.14; found value: 432.2, chiral HPLC retention time = 6.84 minutes ( Chiralpak AS-H, 150x4.6mm, 1 mL/min EtOH). ¹ H-NMR (400MHz, DMSO-d6) δ12.45(br s, 1H), 10.35(t, J=5.8Hz, 1H), 8.44(s, 1H), 7.37(dd, J=15.2, 8.4Hz ,1H),7.23(m,1H),7.05(dt,J=1.8Hz,8.7Hz,1H),5.44(dd,J=9.6,4.0Hz),5.09(br s,1H),4.68(dd, J=12.8,4.0Hz,1H),4.59(br s,1H),4.53(m,2H),4.02(dd,J=12.6,9.4Hz,1H),1.93(br s,4H),1.83(d , J=12.4Hz, 1H), 1.57(m, 1H).

Alternatively, compound 3 was prepared as follows:

Treat 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl) with acetonitrile (5.0 mL) and cis-3-aminocyclopentanol (0.24 g, 2.4 mmol) Methyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (1-C, 1.2 mmol in 5 mL of 9:1 acetonitrile containing 0.026 mL of methanesulfonic acid: in acetic acid). The reaction mixture was sealed and heated to 90 °C. After 30 minutes, the reaction mixture was cooled, treated with potassium carbonate (0.332 g, 2.4 mmol), sealed and reheated to 90 °C. After 15 minutes, the mixture was cooled and partitioned between dichloromethane and hydrochloric acid (0.2M in water). The organic layer was removed, and the aqueous solution was extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate (anhydrous), filtered and concentrated. Purification of the residue by flash chromatography (0-8% ethanol in dichloromethane with 11% saturated aqueous ammonium hydroxide) afforded intermediate 1-D. LCMS-ESI ⁺ (m/z): _C22 [ _M +H] ⁺ _calcd for _H22F2N3O5 : _446.15 ; found: 446.2.

Intermediate 1-D (270 mg) was separated on a 50 mm Chiralpak AD-H column by chiral SFC using 50% (1:1 methanol:acetonitrile) in supercritical carbon dioxide as eluent to give the enantiomers Enriched forms of intermediates 3-A (first eluting peak) and 3-B (second eluting peak). For ₃ -A: LCMS-ESI ⁺ (m/z): [ _{M +} H] ⁺ Calc: _C22H22F2N3O5 : _446.15 ; Found: 446.2. For ₃ -B: LCMS-ESI ⁺ (m/z): [ _{M +} H] ⁺ Calc: _C22H22F2N3O5 : _446.15 ; Found: 446.2.

Intermediate 3-A (0.110 g, 0.247 mmol) in acetonitrile (5 mL) was treated in portions with magnesium bromide (0.091 g, 0.494 mmol), sealed and heated to 50 °C. After 10 minutes, the mixture was cooled and partitioned between dichloromethane and hydrochloric acid (0.2M in water). The organic layer was separated, and the aqueous layer was extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Preparative HPLC purification (30-70% acetonitrile:water, 0.1% TFA) afforded compound 3 in enantiomerically enriched form. Chiral HPLC retention time = 6.51 min (Chiralpak AS-H, 150x found: 432.2.1 H-NMR (44.6 mm, ¹ mL/min EtOH). LCMS-ESI ⁺ (m/z): C ₂₁ H ₂₀ F ₂ N [M+H] ⁺ theoretical value of ₃ O ₅ : 432.14; 00MHz, DMSO-d6) δ12.45 (br s, 1H), 10.35 (t, J = 5.8Hz, 1H), 8.44 (s, 1H), 7.37(dd, J=15.2,8.4Hz,1H),7.23(m,1H),7.05(dt,J=1.8Hz,8.7Hz,1H),5.44(dd,J=9.6,4.0Hz),5.09( brs,1H),4.68(dd,J=12.8,4.0Hz,1H),4.59(brs,1H),4.53(m,2H),4.02(dd,J=12.6,9.4Hz,1H),1.93( br s, 4H), 1.83 (d, J = 12.4Hz, 1H), 1.57 (m, 1H).

Example 4

Preparation of Compound 4

(1S,4R)-N-(2,4-Difluorobenzyl)-7-hydroxy-6,8-dioxo-3,4,6,8,12,12a-hexahydro

-2H-1,4-Methylenepyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

5-(2,4-Difluorobenzylcarbamoyl)-1-(2,2-dihydroxy Ethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid methyl ester (1-C, 0.12 mmol in 0.53 mL of 0.002 mL of methanesulfonic acid 9:1 Acetonitrile: in acetic acid). The reaction mixture was capped and heated to 90°C for 5.5 hours. After cooling, the mixture was partitioned between dichloromethane and sodium bicarbonate (1M in water). The organic layer was separated, and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate (anhydrous), filtered and concentrated. The residue was dissolved in acetonitrile (1 mL), treated with magnesium bromide (0.022 g, 0.12 mmol), capped and heated to 50 °C for 10 min. After cooling, the mixture was partitioned between dichloromethane and ammonium chloride (saturated). The organic layer was separated, and the aqueous layer was extracted again with dichloromethane. The aqueous layer was adjusted to pH = 1 with HCl(aq) and re-extracted with dichloromethane. The aqueous layer was adjusted to pH = 3 with NaOH (aq) and extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Preparative HPLC purification (10-55% acetonitrile:water, 0.1% TFA) afforded compound 4. ¹ H-NMR (400MHz, CD ₃ OD-d4) δ8.42 (s, 1H), 7.42, (q, J = 7.7Hz, 1H), 6.99-6.90 (m, 2H), 5.07 (br s, 1H ),4.73(br d,J=10.8Hz,1H),4.62(s,2H),4.51(br d,J=12.8Hz,1H),4.07(t,J=11.8Hz,1H),3.4-3.0 (m, 3H), 2.76 (br d, J = 8.8Hz, 1H), 2.15-2.0 (m, 1H), 1.9-1.8 (m, 1H). LCMS-ESI ⁺ (m/z): [ _{M +} H] _{+ calcd} for _C20H19F2N4O4 : ^417.14 ; found: 417.2.

Example 5

Preparation of compound 5

(4R,12aS)-N-(1-(2,4-difluorophenyl)cyclopropyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8 ,12,12a-Hexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-9-carboxamide

step 1

(3S,11aR)-6-methoxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole similar to that described in WO2011/119566 And[3,2-d]pyrido[1,2-a]pyrazine-8-carboxylic acid, with (R)-3-aminobutan-1-ol instead of (S)-2-aminopropane- 1 alcohol, preparation of (4R,12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-[1,3 ]oxazino[3,2-d]pyrido[1,2-a]pyrazine-9-carboxylic acid (Intermediate 5-A). The entire content of WO2011/119566 is incorporated herein by reference. Intermediate 5-A (24.8 mg, 0.080 mmol), 1-(2,4-difluorophenyl)cyclopropylamine HCl salt (5-B, 21.9 mg, 0.107 mmol) and HATU (48 mg , 0.126 mmol) in CH ₂ Cl ₂ (2 mL) while N,N-diisopropylethylamine (DIPEA) (0.1 mL, 0.574 mmol) was added. After 30 min, the reaction mixture was diluted with ethyl acetate and washed with 10% aqueous citric acid (x1) and saturated aqueous _NaHCO3 (x1). After extraction of the aqueous fraction with ethyl acetate (xl), the organic portions were combined, dried ( _MgSO4 ) and concentrated. The residue was purified by combiflash (12g column) using hexanes, ethyl acetate and 20% methanol in ethyl acetate to give (4R,12aS)-N-(1-(2,4-difluorophenyl) Cyclopropyl)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-[1,3]oxazino[ 3,2-d]pyrido[1,2-a]pyrazine-9-carboxamide, intermediate 5-C. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Theoretical for C ₂₃ H ₂₄ F ₂ N ₃ O ₅ : 460.17; Found 460.2.

step 2

A suspension of Intermediate 5-C (39 mg, 0.080 mmol) and magnesium bromide (42 mg, 0.2282 mmol) in acetonitrile (2 mL) was stirred at 50 °C. After 1 hour, the reaction mixture was stirred in the bath at 0 °C when 1 N HCl (2 mL) was added. After diluting the resulting mixture with water (-20 mL), the product was extracted with dichloromethane (x3), the combined extracts were dried ( _MgSO4 ) and concentrated. Purification of the residue by preparative HPLC afforded (4R,12aS)-N-(1-(2,4-difluorophenyl)cyclopropyl)-7-hydroxy-4-methyl-6,8-dioxo -3,4,6,8,12,12a-Hexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-9-carboxamide, Compound 5, as a TFA salt. ¹ H-NMR (400MHz, CDCl ₃ ) δ10.72 (br s, 1H), 8.37 (s, 1H), 7.57 (d, J=7.9Hz, 1H), 6.71-6.81 (m, 2H), 5.23 ( dd, J = 5.6 and 4.4Hz, 1H), 4.98 (brquint, J = ~6.5Hz, 1H), 4.26 (dd, J = 13.6 and 4.4Hz, 1H), 4.12 (dd, J = 13.6 and 5.6Hz, 1H), 4.00-4.06(m, 2H), 2.16-2.25(m, 1H), 1.55(br dd, J=13.8 and 1.8Hz, 1H), 1.40(d, J=6.8Hz, 3H), 1.22- 1.31 (m, 4H). ¹⁹ F NMR (376.1 MHz, CDCl ₃ ) δ-76.38 (s, 3F), -111.69～-111.645 (m, 2F). LCMS _- ESI ⁺ (m/z): [ _M +H] ⁺ _calcd for _C22H22F2N3O5 : _446.15 ; found: 446.2.

Example 6

Preparation of compound 6

(1R,4S)-N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-3,4,6,8,12,12a-hexahydro

-2H-1,4-Methylenepyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine- Methyl 2-carboxylate (1-C, 0.100g, 0.243mmol), (S)-pyrrolidin-3-amine (0.043mL, 0.485mmol) and potassium carbonate (0.067g, 0.485mmol) were suspended in acetonitrile (1.9 mL) and acetic acid (0.1 mL) and heated to 90°C for 1.5 hours. After cooling, the mixture was treated with magnesium bromide (0.090 g) and heated to 50°C for 30 minutes. After cooling, the mixture was partitioned between dichloromethane and 0.2M HCl. The organic layer was separated, and the aqueous layer was extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate (anhydrous), filtered and concentrated. Preparative HPLC purification (25-50% acetonitrile:water, 0.1% TFA) afforded compound 6. ¹ H-NMR (400MHz, DMSO-d ₆ ) δ10.33(t, J=6.0Hz, 1H), 8.44(s, 1H), 7.48-7.32(m, 1H), 7.31-7.15(m, 1H) ,7.14-6.97(m,1H),4.86(d,J=2.9Hz,1H),4.62-4.54(m,1H),4.52(d,J=5.9Hz,1H),4.01(d,J=13.0 Hz,1H),2.99-2.76(m,3H),1.96-1.81(m,1H),1.71-1.53(m,1H).LCMS-ESI ⁺ (m/z):C ₂₀ H ₁₉ F ₂ N ₄ [M+H] ⁺ Theoretical for O ₄ : 417.14; Found: 417.2.

Example 7

Preparation of compound 7

(2S,6R)-N-(2,4-Difluorobenzyl)-9-hydroxy-8,10-dioxo-3,4,5,6,8,10,14,14a-octahydro -2H-2,6-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazocine-11-carboxamide

5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine- Methyl 2-carboxylate (1-C, 0.050g, 0.121mmol), (1S,3R)-3-aminocyclohexanol (0.028g, 0.243mmol) and potassium carbonate (0.034g, 0.243mmol) were suspended in acetonitrile (0.95 mL) and heated to 90 °C for 0.5 h. After cooling, acetic acid (0.050 mL) was added, and the mixture was heated to 90° C. for another 2 hours. After cooling, the mixture was treated with magnesium bromide (0.044 g) and heated to 50°C for 1 hour. After cooling, a second portion of magnesium bromide (0.044 g) was added and the mixture was heated to 50°C for a further 15 minutes. After cooling, the mixture was partitioned between dichloromethane and 0.2M HCl. The organic layer was separated, and the aqueous layer was extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate (anhydrous), filtered and concentrated. Preparative HPLC purification (40-80% acetonitrile:water, 0.1% TFA) afforded compound 7. ¹ H-NMR (400MHz, DMSO-d ₆ )δ12.40(s,1H),10.36(t,J=6.1Hz,1H),8.45(s,1H),7.48-7.29(m,1H),7.31 -7.13(m,1H),7.13-6.97(m,1H),5.56(dd,J=10.0,4.1Hz,1H),4.70(dd,J=12.7,4.1Hz,1H),4.52(d,J =5.5Hz, 2H), 4.40-4.29(m, 2H), 4.06(dd, J=12.5, 10.2Hz, 1H), 2.46-2.36(m, 1H), 1.98-1.63(m, 4H), 1.57- 1.30(m,3H). LCMS _- ESI ⁺ (m/z): [ _M +H] ⁺ _calcd for _C22H22F2N3O5 : _446.15 ; found: 446.2.

Example 8

Preparation of compound 8

(2R,6S)-N-(2,4-Difluorobenzyl)-9-hydroxy-8,10-dioxo-3,4,5,6,8,10,14,14a-octahydro -2H-2,6-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazocine-11-carboxamide

Compound 8 was prepared in a manner similar to compound 7, using (1R,3S)-3-aminocyclohexanol instead of (1S,3R)-3-aminocyclohexanol. ¹ H-NMR (400MHz, DMSO-d ₆ )δ12.40(s,1H),10.36(t,J=6.1Hz,1H),8.45(s,1H),7.48-7.30(m,1H),7.23 (td,J=10.6,2.7Hz,1H),7.05(td,J=8.3,2.3Hz,1H),5.56(dd,J=10.1,4.1Hz,1H),4.70(dd,J=12.8,3.9 Hz,1H),4.52(d,J=5.6Hz,2H),4.39-4.27(m,2H),4.06(dd,J=12.6,10.0Hz,1H),2.47-2.35(m,1H),2.00 -1.64(m,4H),1.58-1.30(m,3H).LCMS-ESI ⁺ (m/z): [M+H] ⁺ Theoretical value of C ₂₂ H ₂₂ F ₂ N ₃ O ₅ : 446.15; measured Value: 446.2.

Examples 9 and 10

Preparation of Compounds 9 and 10

(2S,5R,13aS)-N-((R)-1-(4-fluorophenyl)ethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7, 9,13,13a-Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine- 10-carboxamide 9 and (2R,5S,13aR)-N-((R)-1-(4-fluorophenyl)ethyl)-8-hydroxy-7,9-dioxo-2,3, 4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3 ]oxaazepine-10-carboxamide 10

step 1

1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1 -A, 0.500g, 1.59mmol) was suspended in acetonitrile (6mL), and mixed with N,N-diisopropylethylamine (DIPEA) (0.550mL, 3.17mmol), (R)-1-(4-fluorobenzene base) ethylamine (0.242mg, 1.74mmol) and HATU (0.661g, 1.74mmol). The reaction mixture was stirred for 2 hours and partitioned between ethyl acetate and water. The organic layer was separated and washed with HCl (10% aq), sodium bicarbonate (1M aq), dried over sodium sulfate, filtered and concentrated to give crude (R)-1-(2,2-dimethoxyethyl) -5-(1-(4-fluorophenyl)ethylcarbamoyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid methyl ester, which is used for In the next step without purification: LCMS-ESI ⁺ (m/z): [M ₊ H] ⁺ Theoretical: _C21H26FN2O7 : _437.17 ; found: _437.1 .

step 2

(R)-1-(2,2-dimethoxyethyl)-5-(1-(4-fluorophenyl)ethylcarbamoyl)-3-methoxy-4-oxo- Methyl 1,4-dihydropyridine-2-carboxylate was suspended in acetonitrile (5.7 mL) and acetic acid (0.6 mL) and treated with methanesulfonic acid (0.031 mL, 0.477 mmol). The mixture was covered and heated to 75 °C. After 7 hours, the mixture was cooled and used in the next step without purification: LCMS-ESI ⁺ (m/z): [M+H] ⁺ Theoretical: C ₁₉ H ₂₂ FN ₂ O ₇ : 409.14; found Value: 409.0.

step 3

(R)-1-(2,2-dihydroxyethyl)-5-(1-(4-fluorophenyl)ethylcarbamoyl)-3-methoxy-4-oxo-1, Methyl 4-dihydropyridine-2-carboxylate (3.6 mL of the crude mixture from step 2, 0.8 mmol) was diluted with acetonitrile (3.6 mL) and washed with cis-3-aminocyclopentanol, HCl salt (0.219 g, 1.6mmol) and potassium carbonate (0.276g, 2.0mmol). The mixture was covered and heated to 90 °C. After 20 minutes, the reaction mixture was cooled and partitioned between dichloromethane and HCl (0.2 Maq). The layers were separated, and the aqueous layer was extracted again with dichloromethane. The combined organic layers were treated with a small amount of acetonitrile, dried over sodium sulfate, filtered and concentrated.

The residue was suspended in acetonitrile (4 mL) and treated with magnesium bromide (0.177 g). The mixture was covered and heated to 50 °C. After 10 minutes, the reaction mixture was cooled and partitioned between dichloromethane and HCl (0.2 Maq). The organic layer was separated, and the aqueous layer was extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0-8% ethanol:DCM) to give the desired diastereomeric mixture of 9 and 10.

Separation of the mixture by chiral HPLC using Chiralpak AD-H with 100% ethanol as eluent afforded compounds 9 and 10 in enantiomerically enriched form.

[ _M +H] ⁺ Theoretical for compound ₉ : LCMS-ESI ⁺ (m/z): _C22H23FN3O5 : _428.16 ; found: 428.1. Chiral HPLC retention time = 10.177 minutes (Chiralpak AD-H, 150x 4.6mm, 1mL/min EtOH). ¹ H-NMR (400MHz, DMSO-d ₆ ) δ12.45(s, 1H), 10.45(d, J =7.7Hz, 1H), 8.40(s, 1H), 7.37(dd, J=8.6, 5.6Hz, 2H), 7.15(t, J=8.9Hz, 2H), 5.44(dd, J=9.5, 4.2Hz ,1H),5.17-5.04(m,2H),4.73-4.62(m,1H),4.59(s,1H),4.00(dd,J＝12.7,9.5Hz,1H),1.93(s,4H), 1.83(d,J=11.8Hz,1H),1.56(dt,J=12.1,3.4Hz,1H),1.44(d,J=6.9Hz,3H).

For compound 10: LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value for C ₂₂ H ₂₃ FN ₃ O ₅ : 428.16; found value: 428.1. Chiral HPLC retention time = 14.061 minutes (Chiralpak AD -H, 150 x 4.6mm, 1 mL/min EtOH). ¹ H-NMR (400MHz, DMSO-d ₆ ) δ12.44(s, 1H), 10.46(d, J=7.8Hz, 1H), 8.41(s, 1H), 7.37(dd, J=8.6, 5.6Hz ,2H),7.15(t,J=8.9Hz,2H),5.42(dd,J=9.6,4.1Hz,1H),5.18-5.02(m,2H),4.67(dd,J=12.8,4.2Hz, 1H), 4.59(s, 1H), 4.02(dd, J=12.7, 9.6Hz, 1H), 1.93(s, 4H), 1.83(d, J=12.0Hz, 1H), 1.57(dt, J=13.0 , 3.5Hz, 1H), 1.44 (d, J=6.9Hz, 3H).

Example 11

Preparation of Compound 11

(2S,5R,13aS)-N-((R)-1-(2,4-difluorophenyl)ethyl)-8-hydroxy-7,9-dioxo-2,3,4,5 ,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxa Aza-10-carboxamide

step 1

1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1 -A, 0.315g, 1.00mmol) was suspended in acetonitrile (4mL), and mixed with N,N-diisopropylethylamine (DIPEA) (0.348mL, 2.00mmol), (R)-1-(2,4- Difluorophenyl)ethylamine HCl salt (0.213 mg, 1.10 mmol) and HATU (0.418 g, 1.10 mmol) were treated. The reaction mixture was stirred for 1 hour and partitioned between dichloromethane and HCl (10% aq). The organic layer was separated and rinsed with sodium bicarbonate (1 Maq), dried over sodium sulfate, filtered and concentrated to give crude (R)-5-(1-(2,4-difluorophenyl)ethylcarbamoyl)-1 -(2,2-Dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid methyl ester, which was used in the next step without purification . LCMS _- ESI ⁺ (m/z): [M ₊ H] ⁺ _calcd for _C21H25F2N2O7 : _455.16 ; found: 455.1.

step 2

(R)-5-(1-(2,4-difluorophenyl)ethylcarbamoyl)-1-(2,2-dimethoxyethyl)-3-methoxy-4- Oxo-1,4-dihydropyridine-2-carboxylic acid methyl ester was suspended in acetonitrile (3.6 mL) and acetic acid (0.4 mL) and treated with methanesulfonic acid (0.020 mL). The mixture was covered and heated to 75 °C. After 16 hours, the crude mixture was cooled and used in the next step without purification. LCMS _- ESI ⁺ (m/z): [M ₊ H] ⁺ _Calc : _C19H21F2N2O7 : _427.13 ; Found: 427.1.

step 3

(R)-5-(1-(2,4-difluorophenyl)ethylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo- Methyl 1,4-dihydropyridine-2-carboxylate (half of the crude mixture from step 2, about 0.5 mmol) was diluted with acetonitrile (2.5 mL) and washed with (1S,3R)-3-aminocyclopentanol ( 0.110g, 1.09mmol) and potassium carbonate (0.069g, 0.50mmol). The mixture was covered and heated to 90 °C. After 15 minutes, the reaction mixture was cooled and magnesium bromide (0.184 g) was added. The reaction mixture was heated to 50 °C. After 10 minutes, the mixture was cooled and treated with another portion of magnesium bromide (0.184 g). The reaction mixture was reheated to 50 °C and stirred for 10 minutes. After cooling, the mixture was partitioned between dichloromethane and HCl (0.2M aq). The layers were separated, and the aqueous layer was extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Preparative HPLC purification (30-60% acetonitrile:water, 0.1% TFA) afforded the desired compound 11 . LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value of C ₂₂ H ₂₂ F ₂ N ₃ O ₅ : 446.15; measured value: 446.1. ¹ H-NMR (400MHz, DMSO-d ₆ ) δ12 .46(s,1H),10.53(d,J=7.5Hz,1H),8.38(s,1H),7.39(q,J=8.5Hz,1H),7.29-7.12(m,1H),7.13- 6.93(m,1H),5.44(dd,J=9.8,4.2Hz,1H),5.28(p,J=7.3,6.8Hz,1H),5.09(s,1H),4.66(dd,J=13.2, 4.3Hz, 1H), 4.59(s, 1H), 3.99(dd, J=13.1, 9.6Hz, 1H), 1.93(s, 4H), 1.83(d, J=12.4Hz, 1H), 1.56(dt, J=12.5, 2.9Hz, 1H), 1.45(d, J=6.9Hz, 3H).

Example 12

Preparation of Compound 12

(2R,5S,13aR)-N-((R)-1-(2,4-difluorophenyl)ethyl)-8-hydroxy-7,9-dioxo-2,3,4,5 ,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxa Aza-10-carboxamide

Compound 12 was prepared in a similar manner to Compound 11, using (1R,3S)-3-aminocyclopentanol instead of (1S,3R)-3-aminocyclopentanol. ¹ H-NMR (400MHz, DMSO-d ₆ ) δ12.43(s, 1H), 10.52(d, J=8.2Hz, 1H), 8.38(s, 1H), 7.39(q, J=8.4Hz, 1H ),7.28-7.12(m,1H),7.11-6.97(m,1H),5.41(dd,J=10.0,4.0Hz,1H),5.35-5.20(m,1H),5.08(s,1H), 4.65(dd,J=13.1,3.8Hz,1H),4.58(s,1H),4.01(dd,J=12.8,9.5Hz,1H),1.92(s,4H),1.83(d,J=11.5Hz ,1H), 1.61-1.51(m,1H), 1.44(d,J=6.9Hz,3H).LCMS-ESI ⁺ (m/z):[M+H of C ₂₂ H ₂₂ F ₂ N ₃ O ₅ ] ⁺ Theoretical value: 446.15; measured value: 446.1.

Example 13

Preparation of Compound 13

(2S,5R,13aS)-N-((S)-1-(2,4-difluorophenyl)ethyl)-8-hydroxy-7,9-dioxo-2,3,4,5 ,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxa Aza-10-carboxamide

In a similar manner to compound 11, ((S)-1-(2,4-difluorophenyl)ethanamine was used instead of (R)-1-(2,4-difluorophenyl)ethanamine, and only Compound 13 was prepared using a single portion of magnesium bromide (0.184 g). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.44 (s, 1H), 10.53 (d, J=7.8Hz, 1H), 8.39 ( s,1H),7.39(q,J=8.5Hz,1H),7.32-7.14(m,1H),7.05(t,J=9.1Hz,1H),5.42(dd,J=9.5,4.2Hz,1H ),5.29(p,J=6.9Hz,1H),5.09(s,1H),4.65(dd,J=12.9,4.3Hz,1H),4.59(s,1H),4.02(dd,J=12.6, 9.8Hz, 1H), 1.92(s, 4H), 1.83(d, J=12.1Hz, 1H), 1.61-1.52(m, 1H), 1.44(d, J=6.9Hz, 3H).LCMS-ESI ⁺ (m/z): [ _{M +} H] ⁺ Theoretical for _C22H22F2N3O5 : _446.15 ; found: _446.2 .

Example 14

Preparation of compound 14

(2R,5S,13aR)-N-((S)-1-(2,4-difluorophenyl)ethyl)-8-hydroxy-7,9-dioxo-2,3,4,5 ,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxa Aza-10-carboxamide

In a manner similar to compound 11, using ((S)-1-(2,4-difluorophenyl)ethanamine instead of (R)-1-(2,4-difluorophenyl)ethanamine, and using Compound 14 was prepared by replacing (1S,3R)-3-aminocyclopentanol with (1R,3S)-3-aminocyclopentanol. ¹ H-NMR (400MHz, DMSO-d ₆ )δ12.46(s,1H), 10.53(d, J=7.6Hz, 1H), 8.38(s, 1H), 7.39(q, J=8.6Hz, 1H), 7.28-7.14(m, 1H), 7.05(t, J=8.5Hz, 1H ),5.44(dd,J=9.8,3.8Hz,1H),5.28(p,J=8.0Hz,1H),5.09(s,1H),4.66(dd,J=12.9,4.0Hz,1H),4.59 (s,1H),3.99(dd,J=12.5,9.6Hz,1H),1.93(s,4H),1.83(d,J=12.6Hz,1H),1.56(dt,J=13.0,3.3Hz, 1H), 1.45 (d, J=6.9Hz, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value of C ₂₂ H ₂₂ F ₂ N ₃ O ₅ : 446.15; measured value: 446.1.

Example 15

Preparation of Compound 15

(2S,5R,13aS)-N-(4-fluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro- 2,5-Methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

step 1

1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1 suspended in acetonitrile (36 mL) and acetic acid (4 mL) , 4-Dihydropyridine-3-carboxylic acid (1-A, 3.15 g, 10.0 mmol) was treated with methanesulfonic acid (0.195 mL). The mixture was heated to 75°C. After 7 hours, the crude mixture was cooled and stored at -10°C for three days. The crude mixture was heated to 75°C for an additional 2 hours, cooled and used in the next step without purification. LCMS-ESI ⁺ (m/z): [M ₊ H] ⁺ _calcd for _C19H21F2N2O7 : _288.07 ; found: _288.1 .

step 2

Crude 1-(2,2-dihydroxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (16.8mL The crude mixture from step 1, ca. 4 mmol) was mixed with (1S,3R)-3-aminocyclopentanol (0.809 g, 8 mmol), diluted with acetonitrile (16.8 mL) and treated with potassium carbonate (0.553 g, 4 mmol). The reaction mixture was heated to 85°C, stirred for 15 minutes, cooled to ambient temperature and stirred for an additional 16 hours. HCl (50 mL, 0.2 Maq) was added and the clear yellow solution was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated to a yellow solid. The crude material was precipitated from dichloromethane/hexanes to afford the desired intermediate 15-B as a light beige powder. ¹ H-NMR (400MHz, DMSO-d ₆ ) δ8.72(s, 1H), 5.42(dd, J=9.6, 4.1Hz, 1H), 5.09(s, 1H), 4.72(dd, J=13.0, 3.7Hz, 1H), 4.57(s, 1H), 4.09(dd, J=12.5, 9.6Hz, 1H), 3.83(s, 3H), 1.92(s, 3H), 1.78(m, 2H), 1.62- 1.47 (m, 1H). LCMS-ESI ⁺ (m/z): _[ M ₊ H] ⁺ Calc for _C15H17N2O6 : _321.11 ; found: 321.2.

step 3

Intermediate 15-B (0.040g, 0.125mmol) and (4-fluorophenyl)methanamine (0.017g, 0.137mmol) were suspended in acetonitrile (1 mL) and washed with N,N-diisopropylethylamine ( DIPEA) (0.033 mL, 0.187 mmol) and HATU (0.052 g, 0.137 mmol). After stirring for 30 minutes, the reaction mixture was treated with magnesium bromide (0.046 g, 0.25 mmol) and heated to 50 °C. After 10 minutes, the reaction mixture was cooled and treated with HCl (2 mL, 10% aq). After a few minutes, the precipitate was filtered and washed with HCl (10% aq) and water. Preparative HPLC purification (20-65% acetonitrile:water, 0.1% TFA) of the precipitate afforded the desired compound 15. ¹ H-NMR (400MHz, DMSO-d ₆ ) δ12.44(s, 1H), 10.36(t, J=6.0Hz, 1H), 8.46(s, 1H), 7.37-7.28(m, 2H), 7.19 -7.09(m,2H),5.43(dd,J=9.6,4.0Hz,1H),5.08(s,1H),4.68(dd,J=12.8,4.1Hz,1H),4.59(s,1H), 4.58-4.42(m,3H),4.02(dd,J=12.7,9.6Hz,1H),1.92(s,5H),1.83(d,J=12.2Hz,1H),1.56(dt,J=12.0, 3.4Hz, 1H). LCMS _- ESI ⁺ (m/z): [ _M +H] ⁺ calcd for _C21H21FN3O5 : _414.15 ; found: 414.2.

Example 16

Preparation of compound 16

(2S,5R,13aS)-N-(2,3-Difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a- Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Compound 16 was prepared in a manner similar to compound 15, using (2,3-difluorophenyl)methylamine instead of (4-fluorophenyl)methylamine. ¹ H-NMR (400MHz, DMSO-d ₆ )δ12.46(s,1H),10.41(t,J=6.1Hz,1H),8.45(s,1H),7.43-7.25(m,1H),7.25 -7.05(m,2H),5.44(dd,J=9.5,3.9Hz,1H),5.09(s,1H),4.68(dd,J=12.8,4.0Hz,1H),4.65-4.53(m,3H ),4.02(dd,J=12.7,9.8Hz,1H),3.56(s,1H),1.93(s,4H),1.83(d,J=11.9Hz,1H),1.57(dt,J=11.5, 3.0Hz, 1H). LCMS _- ESI ⁺ (m/z): [ _M +H] ⁺ _calcd for _C21H20F2N3O5 : _432.14 ; found: 432.2.

Example 17

Preparation of compound 17

(2S,5R,13aS)-N-(4-Chloro-2-fluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a -Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Compound 17 was prepared in a manner similar to compound 15, using (4-chloro-2-fluorophenyl)methylamine instead of (4-fluorophenyl)methylamine. ¹ H-NMR (400MHz,DMSO-d ₆ )δ12.46(s,1H),10.45-10.29(m,1H),8.44(s,1H),7.42(dd,J=10.0,2.0Hz,1H) ,7.33(t,J=8.1Hz,1H),7.26(dd,J=8.4,1.8Hz,1H),5.50-5.38(m,1H),5.09(s,1H),4.68(dd,J=13.0 ,4.0Hz,1H),4.59(s,1H),4.54(m,2H),4.02(dd,J=12.8,9.7Hz,1H),1.93(s,4H),1.83(d,J=12.0Hz , 1H), 1.57 (dt, J=11.9, 3.4Hz, 1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value of C ₂₁ H ₂₀ ClFN ₃ O ₅ : 448.11; measured value : 448.2.

Example 18

Preparation of Compound 18

(2S,5R,13aS)-N-(3,4-Difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a- Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Compound 18 was prepared in a manner similar to compound 15, using (3,4-difluorophenyl)methylamine instead of (4-fluorophenyl)methylamine. ¹ H-NMR (400MHz,DMSO-d ₆ )δ12.46(s,1H),10.51-10.27(m,1H),8.46(s,1H),7.50-7.23(m,2H),7.23-7.03( m,1H),5.44(dd,J＝9.5,3.6Hz,1H),5.09(s,1H),4.75-4.63(m,1H),4.60(s,1H),4.57-4.44(m,2H) ,4.02(dd,J=12.6,9.8Hz,1H),1.93(s,4H),1.83(d,J=12.0Hz,1H),1.57(dt,J=12.0,3.4Hz,1H).LCMS- ESI ⁺ (m/z): [ _M +H] ⁺ _calcd for _C21H20F2N3O5 : _432.14 ; found: _432.2 .

Example 19

Preparation of compound 19

(1R,5S)-N-(2,4-Difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro -1,5-Methylenepyrido[1',2':4,5]pyrazino[1,2-a][1,3]diaza-10-carboxamide

Steps 1 and 2

5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine- Methyl 2-carboxylate (1-C, 97.5mg, 0.236mmol) was distilled with acetonitrile (1.9mL), acetic acid (0.1mL), potassium carbonate (145mg, 1.05mmol) and (S)-piperidin-3-amine Treated with hydrochloride (82mg, 0.472mmol). The reaction mixture was sealed and heated to 90 °C. After 60 minutes, the reaction mixture was cooled, partitioned between brine and dichloromethane. The aqueous phase was extracted three times into dichloromethane and the combined organic phases were combined, dried over _MgSO4 , filtered and concentrated. The crude product was dissolved in acetonitrile (2 mL), and magnesium bromide (89.1 mg, 0.48 mmol) was added. The mixture was resealed and heated to 50 °C. After 80 min, the reaction mixture was quenched with ~5 mL of 0.2M HCl(aq), adjusted to pH ~10, diluted with brine, and extracted three times into DCM. HPLC (acetonitrile:water, 0.1% TFA) gave compound 19. ¹ H-NMR (400MHz, chloroform-d) δ10.43(t, J=5.9Hz, 1H), 8.43(s, 1H), 7.39-7.30(m, 1H), 6.81(q, J=8.1Hz, 2H), 4.89(dd, J=11.6, 3.8Hz, 1H), 4.69(s, 1H), 4.64(d, J=5.8Hz, 2H), 4.26(dd, J=12.6, 3.8Hz, 1H), 3.91(t,J=12.1Hz,1H),3.20-3.10(m,2H),3.06(s,2H),2.14-2.02(m,1H),1.96-1.81(m,2H),1.81-1.70( m,1H). LCMS-ESI ⁺ (m/z ^{): [M+H]+} _{Theoretical for C21H20F2N4O4 : 431.15} ; found: 431.2.

Example 20

Preparation of Compound 20

(1S,5R)-N-(2,4-Difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro -1,5-Methylenepyrido[1',2':4,5]pyrazino[1,2-a][1,3]diaza-10-carboxamide

Steps 1 and 2

5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine- Methyl 2-carboxylate (1-C, 103.3mg, 0.25mmol) was mixed with (1.9mL), acetic acid (0.1mL), potassium carbonate (159.8mg, 1.16mmol) and (R)-piperidin-3-amine di Hydrochloride (90mg, 0.52mmol) treatment. The reaction mixture was sealed and heated to 90 °C. After 40 minutes, the reaction mixture was partitioned between brine and dichloromethane. The aqueous phase was extracted three times into dichloromethane and the combined organic phases were combined, dried over _MgSO4 , filtered and concentrated. The crude product was dissolved in acetonitrile (2 mL), and magnesium bromide (96.5 mg, 0.52 mmol) was added. The mixture was resealed and heated to 50 °C. After 80 min, the reaction mixture was quenched with ~5 mL of 0.2M HCl(aq), adjusted to pH ~10, diluted with brine, and extracted three times into DCM. HPLC (acetonitrile:water, 0.1% TFA) gave compound 20. ¹ H-NMR (400MHz, DMSO-d ₆ ) δ10.35(t, J=6.0Hz, 1H), 8.48(s, 1H), 7.45-7.33(m, 1H), 7.29-7.18(m, 1H) ,7.05(td,J=8.5,2.4Hz,1H),5.06(dd,J=11.4,3.5Hz,1H),4.56-4.47(m,3H),4.44(s,1H),4.05(t,J =11.8Hz, 1H), 3.07-2.89(m, 4H), 1.85-1.73(m, 3H), 1.54-1.46(m, 1H). LCMS-ESI ⁺ (m/z): C ₂₁ H ₂₀ F ₂ [M ₊ H] ₊ Theoretical for ^N4O4 : 431.15; found: 431.2.

Example 21

Preparation of compound 21

(2S,5R,13aS)-N-((S)-1-(4-fluorophenyl)ethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7, 9,13,13a-Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine- 10-Formamide

Steps 1 and 2

(S)-1-(2,2-Dihydroxyethyl)-5-(1 -(4-fluorophenyl)ethylcarbamoyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid methyl ester (21-A, 1 mL, at 19: 1 Acetonitrile: 0.23M solution in acetic acid according to (R)-1-(2,2-dihydroxyethyl)-5-(1-(4-fluorophenyl)ethylcarbamoyl from Example 9 )-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid methyl ester 9-A, using (S)-1-(4-fluorophenyl)ethylamine instead of ( R)-1-(4-fluorophenyl)ethylamine). The reaction mixture was sealed and heated to 90 °C. After 60 minutes, the reaction mixture was cooled, partitioned between brine and dichloromethane. The aqueous phase was extracted three times into dichloromethane, and the combined organic phases were combined, dried over _MgSO4 , filtered and concentrated. The crude product was dissolved in acetonitrile (2 mL), and magnesium bromide (74 mg, 0.4 mmol) was added. The mixture was resealed and heated to 50 °C. After 100 minutes, the reaction mixture was quenched with 0.2M HCl (aq), diluted with brine, and extracted three times into DCM. HPLC purification (acetonitrile:water, 0.1% TFA) afforded compound 21. ¹ H-NMR (400MHz, DMSO-d ₆ )δ12.42(br s,1H),10.45(d,J=7.9Hz,1H),8.40(s,1H),7.36(dd,J=8.6,5.5 Hz, 2H), 7.14(t, J=8.9Hz, 2H), 5.42(dd, J=9.6, 4.2Hz, 1H), 5.15-5.04(m, 2H), 4.72-4.55(m, 2H), 4.02 (dd, J=12.7,9.7Hz,1H),1.97-1.89(m,4H),1.82(d,J=12.2Hz,1H),1.56(dt,J=11.9,3.3Hz,1H),1.43( d, J = 6.9 Hz, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical for C ₂₂ H ₂₂ FN ₃ O ₅ : 428.16; found: 428.1.

Example 22

Preparation of Compound 22

(2R,5S,13aR)-N-((S)-1-(4-fluorophenyl)ethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7, 9,13,13a-Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine- 10-Formamide

Steps 1 and 2

(S)-1-(2,2-Dihydroxyethyl)-5-(1 -(4-fluorophenyl)ethylcarbamoyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid methyl ester (21-A, 1 mL, at 19: 1 acetonitrile:0.23M solution in acetic acid). The reaction mixture was sealed and heated to 90 °C. After 60 minutes, the reaction mixture was cooled, partitioned between brine and dichloromethane. The aqueous phase was extracted three times into dichloromethane, and the combined organic phases were combined, dried over _MgSO4 , filtered and concentrated. The crude product was dissolved in acetonitrile (2 mL), and magnesium bromide (91 mg, 0.49 mmol) was added. The reaction mixture was sealed and heated to 50 °C. After 100 minutes, the reaction mixture was quenched with 0.2M HCl (aq), diluted with brine, and extracted three times into DCM. HPLC purification (acetonitrile:water, 0.1% TFA) gave compound 22. ¹ H-NMR (400MHz, DMSO-d ₆ ) δ12.44 (br s, 1H), 10.45 (d, J = 7.7Hz, 1H), 8.39 (s, 1H), 7.36 (dd, J = 8.5, 5.6 Hz, 2H), 7.14(t, J=8.9Hz, 2H), 5.43(dd, J=9.6, 4.0Hz, 1H), 5.15-5.06(m, 2H), 4.66(dd, J=12.8, 3.9Hz ,1H),4.58(s,1H),3.99(dd,J=12.6,9.5Hz,1H),1.93(s,4H),1.82(d,J=12.0Hz,1H),1.56(dt,J= 12.0, 3.0Hz, 1H), 1.44 (d, J=6.9Hz, 3H). LCMS _- ESI ⁺ (m/z): [ _M +H] ⁺ calcd for _C22H22FN3O5 : _428.16 ; found: 428.1.

Example 23

Preparation of compound 23

(2S,5R,13aS)-N-(2-Fluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro- 2,5-Methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Steps 1 and 2

Treat with acetonitrile (1 mL), (2-fluorophenyl)methylamine (17 mg, 0.14 mmol), HATU (67 mg, 0.18 mmol) and N,N-diisopropylethylamine (DIPEA) (24 mg, 0.19 mmol) 15-B (41 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 1 hour, and magnesium bromide (47 mg, 0.26 mmol) was added. The mixture was sealed and heated to 50 °C. After 60 minutes, the reaction mixture was quenched with 0.2M HCl (aq), diluted with brine, and extracted three times into DCM. HPLC purification (acetonitrile:water, 0.1% TFA) gave compound 23. ¹ H-NMR (400MHz, chloroform-d) δ10.42(s, 1H), 8.34(s, 1H), 7.36(t, J=7.9Hz, 1H), 7.24-7.17(m, 1H), 7.12- 6.97(m,2H),5.40-5.32(m,1H),5.29(t,J＝3.5Hz,1H),4.67(s,3H),4.28-4.20(m,1H),4.06-3.95(m, 1H), 2.20-1.96(m, 4H), 1.95-1.84(m, 1H), 1.59(dt, J=12.4, 3.3Hz, 1H). LCMS-ESI ⁺ (m/z): C ₂₁ H ₂₀ FN [M+H] ⁺ Theoretical for ₃ O ₅ : 414.15; Found: 414.2.

Example 24

Preparation of Compound 24

(2S,5R,13aS)-N-(3,5-Difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a- Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Steps 1 and 2

Treat with acetonitrile (1 mL), (3,5-difluorophenyl)methanamine (32 mg, 0.23 mmol), HATU (54 mg, 0.14 mmol) and N,N-diisopropylethylamine (37 mg, 0.29 mmol) 15-B (44 mg, 0.14 mmol). The reaction mixture was stirred at room temperature for 1 hour, and magnesium bromide (57 mg, 0.31 mmol) was added. The mixture was sealed and heated to 50 °C. After 60 minutes, the reaction mixture was quenched with 0.2M HCl (aq), diluted with brine, and extracted three times into DCM. HPLC purification (acetonitrile:water, 0.1% TFA) afforded compound 24. ¹ H-NMR (400MHz, chloroform-d) δ10.39(s, 1H), 8.42(s, 1H), 6.82(d, J=7.9Hz, 2H), 6.65(t, J=8.8Hz, 1H) ,5.38(d,J=7.7Hz,1H),5.28(s,1H),4.78-4.41(m,3H),4.32(d,J=12.1Hz,1H),4.02(t,J=10.9Hz, 1H), 2.30-1.97 (m, 4H), 1.97-1.81 (m, 1H), 1.59 (d, J=12.3Hz, 1H). LCMS _- ESI ⁺ (m/z): [ _M +H] ⁺ _calcd for _C21H19F2N3O5 : _432.14 ; found: 432.2.

Example 25

Preparation of compound 25

(2S,5R,13aS)-N-(4-fluoro-3-(trifluoromethyl)benzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7, 9,13,13a-Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine- 10-Formamide

Steps 1 and 2

With acetonitrile (1 mL), (4-fluoro-3-(trifluoromethyl)phenyl)methanamine (29 mg, 0.15 mmol), HATU (62 mg, 0.16 mmol) and N,N-diisopropylethylamine ( 26 mg, 0.20 mmol) was treated with 15-B (43 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 1 hour, and magnesium bromide (62 mg, 0.34 mmol) was added. The mixture was sealed and heated to 50 °C. After 60 minutes, the reaction mixture was quenched with 0.2M HCl (aq), diluted with brine, and extracted three times into DCM. Purification by HPLC (acetonitrile:water, 0.1% TFA) afforded compound 25. ¹ H-NMR (400MHz, chloroform-d) δ10.44(s, 1H), 8.29(s, 1H), 7.56-7.38(m, 2H), 7.06(t, J=9.2Hz, 1H), 5.30( dd,J=9.3,3.5Hz,1H),5.21(s,1H),4.65-4.45(m,3H),4.21(dd,J=12.8,3.4Hz,1H),3.95(dd,J=12.4, ₂₂ ^_ [ _M +H] ⁺ calcd for _H19F4N3O5 : _482.14 ; found: _482.2 .

Example 26

Preparation of compound 26

(2S,5R,13aS)-N-(4-Chloro-3-fluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a -Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Steps 1 and 2

With acetonitrile (1 mL), (4-chloro-3-fluorophenyl)methanamine (40mg, 0.25mmol), HATU (60mg, 0.16mmol) and N,N-diisopropylethylamine (28mg, 0.22mmol) Treated 15-B (41 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 1 hour, and magnesium bromide (48 mg, 0.26 mmol) was added. The mixture was sealed and heated to 50 °C. After 60 minutes, the reaction mixture was quenched with 0.2M HCl (aq), diluted with brine, and extracted three times into DCM. Purification by HPLC (acetonitrile:water, 0.1% TFA) afforded compound 26. ¹ H-NMR (400MHz, chloroform-d) δ10.41(s, 1H), 8.30(s, 1H), 7.24(t, J=6.1Hz, 1H), 7.13-6.90(m, 2H), 5.30( dd,J=9.1,3.2Hz,1H),5.22(s,1H),4.61(s,1H),4.51(s,2H),4.20(d,J=9.4Hz,1H),3.95(d,J =12.0Hz, 1H), 2.11-1.90(m, 4H), 1.90-1.76(m, 1H), 1.53(d, J=12.2Hz, 1H).LCMS-ESI ⁺ (m/z): C ₂₁ H [M+H] ⁺ calc for ₁₉ ClFN ₃ O ₅ : 448.11; found: 448.2.

Example 27

Preparation of compound 27

(2S,5R)-N-(1-(2,4-difluorophenyl)cyclopropyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9, 13,13a-Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10- Formamide

step 1

A suspension of compound 1-A (1.004 g, 3.19 mmol), amine 27-A (688 mg, 3.35 mmol) and HATU (1.453 g 3.82 mmol) in _CH2Cl2 ( ₂₀ mL) was stirred in a 0 °C bath, N,N-Diisopropylethylamine (DIPEA) (2 mL, 11.48 mmol) was added simultaneously. After 1 hour at 0 °C, the reaction mixture was concentrated to a slurry, diluted with ethyl acetate, and washed with water (x2). After extracting the aqueous fraction with ethyl acetate ( _xl ), the organic portions were combined, dried ( _Na2SO4 ) and concentrated. The residue was purified by CombiFlash (120 g column) using hexane-ethyl acetate as eluent. The major peaks were combined and concentrated to give 1.082 (73%) of product 27-B. After minor peaks _were combined and concentrated, the concentrated residue was dissolved in _CH2Cl2 and some insoluble material was filtered off. The filtrate was concentrated to afford 361 mg (24%) of additional product 27-B. LCMS _- ESI ⁺ (m/z): [M ₊ H] ⁺ _calcd for _C22H25F2N2O7 : _467.16 ; found: 467.1.

Steps 2 and 3

Compound 27-B (81 mg, 0.174 mmol) was dissolved in a mixture (1 mL) of acetonitrile (22 mL), AcOH (2 mL) and methanesulfonic acid (0.14 mL, 2.16 mmol) at room temperature and stirred at 65 °C The resulting solution was 20 hours.

After the resulting solution was cooled to room temperature, aminoalcohol 27-D (50 mg, racemic, 0.363 mmol), K ₂ CO ₃ (50 mg, 0.362 mmol) and acetonitrile (2 mL) were added to the solution. The resulting mixture was stirred in a 65°C bath for 1 hour. After cooling the reaction mixture to room temperature, it was acidified with 1 N HCl (~2 mL), diluted with water (~8 mL), and extracted with _CH2Cl2 (x ₃ ). The combined extracts were dried (Na ₂ SO ₄ ), concentrated and purified by CombiFlash to afford 67 mg (82%) of compound 27-E. ¹ H-NMR (400MHz, CDCl ₃ ) δ10.53(s, 1H), 8.25(s, 1H), 7.60(td, J=8.5, 6.5Hz, 1H), 6.85-6.57(m, 2H), 5.33 (br,1H),5.26(dd,J=9.6,3.9Hz,1H),4.60(t,J=3.0Hz,1H),4.18-4.06(m,1H),4.01(s,3H),3.92( dd, J=12.7, 9.6Hz, 1H), 2.11-1.91(m, 4H), 1.88-1.71(m, 1H), 1.60-1.49(m, 1H), 1.31-1.10(m, 4H). ¹⁹ F-NMR (376.1MHz, CDCl ₃ ) δ -111.80 (q, J=8.8Hz, 1F), -112.05 (p, J=7.9Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value for C ₂₄ H ₂₄ F ₂ N ₃ O ₅ : 472.17; found value: 472.1.

step 4

A mixture of compound 27-E (67 mg, 0.142 mmol) and MgBr2 (66 _mg , 0.358 mmol) in MeCN (3 mL) was stirred at 50 °C for 30 min and cooled to 0 °C before being treated with 1 N HCl (3 mL) . After diluting the mixture with water (-30 mL), the product was extracted with _{CH2Cl2 (} x3), the combined extracts were dried ( _{Na2SO4 )} and concentrated. The product was purified by preparative HPLC and lyophilized to give product 27 as a 1:1 mixture with trifluoroacetic acid. ¹ H-NMR (400MHz, CDCl ₃ ) δ10.70(s, 1H), 8.35(s, 1H), 7.57(q, J=8.2Hz, 1H), 6.91-6.56(m, 2H), 5.31(dt ,J=14.3,4.0Hz,2H),4.68(s,1H),4.22(dd,J=13.2,3.9Hz,1H),3.99(dd,J=12.8,9.3Hz,1H),2.28-1.96( m, 5H), 1.88(ddt, J=12.1, 8.6, 3.7Hz, 1H), 1.71-1.49(m, 1H), 1.38-1.11(m, 4H). ¹⁹ F-NMR(376.1MHz, CDCl ₃ ) δ-76.37(s,3F),-111.6～-111.75(m,2F). LCMS _- ESI ⁺ (m/z): [ _M +H] ⁺ _calcd for _C23H22F2N3O5 : _458.15 ; found: 458.1.

Example 28

Preparation of Compound 28

(2S,6R)-N-(1-(2,4-difluorophenyl)cyclopropyl)-9-hydroxy-8,10-dioxo-3,4,5,6,8,10, 14,14a-Octahydro-2H-2,6-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazocine-11-methano Amide

Steps 1 and 2

Compound 27-B (87 mg, 0.187 mmol) was dissolved in a mixture (2 mL) of acetonitrile (22 mL), AcOH (2 mL) and methanesulfonic acid (0.14 mL, 2.16 mmol) at room temperature and stirred at 65 °C The resulting solution was 20 hours.

After the resulting solution was cooled to room temperature, aminoalcohol 28-A (44 mg, racemic, 0.382 mmol) and acetonitrile (2 mL) were added to the solution. After stirring the resulting mixture in a 65 °C bath for ₃₀ min, K2CO3 (41 _mg , 0.297 mmol) was added and the mixture was stirred at 65 °C for 21 h. The reaction mixture was cooled to room temperature, acidified with 1N HCl (~2 mL), diluted with water (~8 mL), and extracted with _{CH2Cl2 (} x3). The combined extracts were dried ( _{Na2SO4 )} , concentrated and purified by preparative HPLC, and fractions containing product were lyophilized. After the residue was dissolved in ethyl acetate, the solution was washed with sat. NaHCO ₃ (×1), dried (Na ₂ SO ₄ ) and concentrated to afford 18 mg (20%) of compound 28-B in the form of trifluoro 1:1 mixture of acetic acid. ¹ H-NMR (400MHz, CDCl ₃ ) δ10.54(s, 1H), 8.26(s, 1H), 7.63(td, J=8.6, 6.6Hz, 1H), 6.76(dddd, J=21.9, 11.2, 8.7,2.3Hz,2H),5.39(dd,J＝9.6,3.7Hz,1H),4.53-4.36(m,2H),4.09(dd,J＝12.8,3.7Hz,1H),4.03(s,3H ), 3.99(dd, J＝12.7, 9.7Hz, 1H), 2.41-2.20(m, 2H), 1.84(dtd, J＝19.7, 9.3, 8.8, 4.4Hz, 2H), 1.74(dd, J＝14.6 ,2.5Hz,1H),1.62-1.35(m,2H),1.34-1.14(m,5H) ^.19F -NMR(376.1MHz,CDCl ₃ )δ-111.75(q,J＝8.9Hz,1F), -112.01 (p, J=7.9Hz, 1F). LCMS _- ESI ⁺ (m/z): [ _M +H] ⁺ _calcd for _C25H26F2N3O5 : _486.18 ; found: 486.2.

step 3

Compound 28-B (18 mg, 0.037 mmol) was treated with MgBr ₂ to afford compound 28 as described in step 4 for the synthesis of compound 27-E. ¹ H-NMR (400MHz, CDCl ₃ ) δ10.66(s, 1H), 8.29(s, 1H), 7.59(td, J=8.5, 6.6Hz, 1H), 6.89-6.60(m, 2H), 5.51 (dd, J=9.9,4.0Hz,1H),4.55(s,1H),4.48(t,J=4.2Hz,1H),4.21(dd,J=12.9,4.1Hz,1H),3.99(dd, J=12.8,9.8Hz,1H),2.56-2.35(m,1H),2.14(dd,J=16.1,5.9Hz,1H),1.96-1.74(m,3H),1.66-1.37(m,3H) , 1.28 (d, J=4.4Hz, 2H), 1.26-1.19 (m, 2H). ¹⁹ F-NMR (376.1 MHz, CDCl ₃ ) δ-76.41 (s, 3F, -111.79 (m, 2F). LCMS - ESI ⁺ (m/z): [M+H] ⁺ calcd for C ₂₄ H ₂₃ F ₂ N ₃ O ₅ : 472.17; found: 472.1.

Example 29

Preparation of compound 29

(2R,6S)-N-(1-(2,4-difluorophenyl)cyclopropyl)-9-hydroxy-8,10-dioxo-3,4,5,6,8,10, 14,14a-Octahydro-2H-2,6-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazocine-11-methano Amide

Steps 1 and 2

Compound 29-B (13 mg, 14 %). ¹ H-NMR (400MHz, CDCl ₃ ) δ10.54(s, 1H), 8.26(s, 1H), 7.63(td, J=8.6, 6.6Hz, 1H), 6.76(dddd, J=21.9, 11.2, 8.7,2.3Hz,2H),5.39(dd,J＝9.6,3.7Hz,1H),4.53-4.36(m,2H),4.09(dd,J＝12.8,3.7Hz,1H),4.03(s,3H ), 3.99(dd, J＝12.7, 9.7Hz, 1H), 2.41-2.20(m, 2H), 1.84(dtd, J＝19.7, 9.3, 8.8, 4.4Hz, 2H), 1.74(dd, J＝14.6 ,2.5Hz,1H),1.62-1.35(m,2H),1.34-1.14(m,5H). ¹⁹ F-NMR (376.1MHz, CDCl ₃ ) δ -111.75 (q, J=8.9Hz, 1F), -112.01 (p, J=7.9Hz, 1F). LCMS _- ESI ⁺ (m/z): [ _M +H] ⁺ _calcd for _C25H26F2N3O5 : _486.18 ; found: 486.2.

step 3

Compound 29 was prepared from compound 29-B in a manner similar to that described in Step 2 for the synthesis of compound 16. ¹ H-NMR (400MHz, CDCl ₃ ) δ10.66(s, 1H), 8.29(s, 1H), 7.59(td, J=8.5, 6.6Hz, 1H), 6.89-6.60(m, 2H), 5.51 (dd, J=9.9,4.0Hz,1H),4.55(s,1H),4.48(t,J=4.2Hz,1H),4.21(dd,J=12.9,4.1Hz,1H),3.99(dd, J=12.8,9.8Hz,1H),2.56-2.35(m,1H),2.14(dd,J=16.1,5.9Hz,1H),1.96-1.74(m,3H),1.66-1.37(m,3H) , 1.28 (d, J=4.4Hz, 2H), 1.26-1.19 (m, 2H). ¹⁹ F-NMR (376.1 MHz, CDCl ₃ ) δ-76.41 (s, 3F, -111.79 (m, 2F). LCMS - ESI ⁺ (m/z): [M+H] ⁺ calcd for C ₂₄ H ₂₃ F ₂ N ₃ O ₅ : 472.17; found: 472.1.

Example 30

Preparation of compound 30

(2S,5R,13aS)-N-(1-(2,4-difluorophenyl)cyclopropyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7, 9,13,13a-Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine- 10-Formamide

Steps 1 and 2

Compound 27-B (150 mg, 0.322 mmol) was dissolved in acetonitrile (2 mL), AcOH (0.2 mL) and methanesulfonic acid (0.007 mL, 0.108 mmol) at room temperature, and the resulting solution was stirred at 65 °C for 20 Hour. After cooling the resulting solution to room temperature, aminoalcohol 30-A (72.1 mg, chiral, 0.713 mmol), K ₂ CO ₃ (89.4 mg, 0.647 mmol) and acetonitrile (2 mL) were added to the solution. The resulting mixture was stirred in a 65°C bath for 0.5 hours. After cooling the reaction mixture to room temperature, it was acidified with 1N HCl (~3 mL), diluted with water (~12 mL), and extracted with _{CH2Cl2 (} x3). The combined extracts were dried (Na ₂ SO ₄ ), concentrated and purified by CombiFlash to afford 128 mg (84%) of compound 30-B. ¹ H-NMR (400MHz, CDCl ₃ ) δ10.52(s, 1H), 8.24(s, 1H), 7.61(td, J=8.6, 6.6Hz, 1H), 6.85-6.65(m, 2H), 5.33 (t, J=4.1Hz, 1H), 5.25(dd, J=9.5, 3.9Hz, 1H), 4.61(d, J=3.4Hz, 1H), 4.18-4.08(m, 1H), 4.02(s, 3H),3.99-3.87(m,1H),2.12-1.91(m,4H),1.85-1.69(m,1H),1.55(ddd,J＝12.3,4.1,2.8Hz,1H),1.31-1.14( m, 4H). ¹⁹ F-NMR (376.1MHz, CDCl ₃ ) δ-111.79 (q, J = 8.8Hz, 1F), -112.05 (p, J = 7.9Hz, 1F). LCMS-ESI ⁺ (m/ z): [ _{M +} H] ⁺ _Calc for _C24H24F2N3O5 : _472.17 ; found: 472.2.

step 3

A mixture of compound 30-B (128 mg, 0.272 mmol) and MgBr2 (130 _mg , 0.706 mmol) in MeCN (5 mL) was stirred at 50 °C for 30 min and cooled to 0 °C before being treated with 1 N HCl (4 mL) . After diluting the mixture with water, the product was extracted with _{CH2Cl2 (} x3), the combined extracts were dried ( _{Na2SO4 )} and concentrated. The product was purified by CombiFlash to give product 30. ¹ H-NMR (400MHz, CDCl ₃ )δ12.27(s,1H),10.52(s,1H),8.16(s,1H),7.61(td,J＝8.6,6.6Hz,1H),6.96-6.54 (m,2H),5.36-5.23(m,2H),4.66(t,J=3.1Hz,1H),4.18-4.06(m,1H),3.94(dd,J=12.8,9.4Hz,1H), 2.20-1.95 (m, 4H), 1.89 (td, J=11.4, 9.8, 6.7Hz, 1H), 1.70-1.54 (m, 1H), 1.32-1.15 (m, 4H). ¹⁹ F-NMR (376.1MHz, CDCl ₃ ) δ -111.87 (q, J=8.9Hz, 1F), -112.21 (p, J=7.9Hz, 1F). LCMS _- ESI ⁺ (m/z): [ _M +H] ⁺ _calcd for _C23H22F2N3O5 : _458.15 ; found: 458.2.

Example 31

Preparation of compound 31

(2R,5S)-N-(1-(2,4-difluorophenyl)cyclopropyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9, 13,13a-Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10- Formamide

Steps 1 and 2

Compound 31-B (123 mg , 81%). ¹ H-NMR (400MHz, CDCl ₃ ) δ10.52(s, 1H), 8.24(s, 1H), 7.62(td, J=8.6, 6.6Hz, 1H), 6.91-6.63(m, 2H), 5.33 (t,J=4.1Hz,1H),5.25(dd,J=9.5,3.9Hz,1H),4.61(d,J=3.4Hz,1H),4.14-4.07(m,1H),4.03(s, 3H), 3.93(dd, J＝12.7, 9.5Hz, 1H), 2.12-1.91(m, 4H), 1.85-1.69(m, 1H), 1.55(ddd, J＝12.3, 4.1, 2.8Hz, 1H) ,1.31-1.14(m,4H). ¹⁹ F-NMR (376.1MHz, CDCl ₃ )δ-111.79(q,J=9.2,8.7Hz,1F),-112.03(h,J=8.1,7.5Hz,1F ). LCMS _- ESI ⁺ (m/z): [ _M +H] ⁺ _calcd for _C24H24F2N3O5 : _472.17 ; found: 472.1.

step 3

Compound 31 was prepared from Compound 31-B in a manner similar to that described in Step 3 for the synthesis of Compound 30. ¹ H-NMR (400MHz, CDCl ₃ )δ12.26(s,1H),10.49(s,1H),8.13(s,1H),7.58(td,J＝8.6,6.5Hz,1H),6.90-6.56 (m,2H),5.32(dd,J=9.4,4.1Hz,1H),5.27-5.22(m,1H),4.64(t,J=3.1Hz,1H),4.11(dd,J=12.8,4.0 Hz,1H),4.01-3.79(m,1H),2.28-1.95(m,4H),1.95-1.80(m,1H),1.71(m,1H),1.56(m,1H),1.42-1.08( m, 4H). ¹⁹ F-NMR (376.1MHz, CDCl ₃ ) δ-111.95 (q, J = 8.9Hz, 1F), -112.22 (p, J = 7.9Hz, 1F). LCMS-ESI ⁺ (m/ z): [M+H] ⁺ Calc for C ₂₃ H ₂₂ F ₂ N ₃ O ₅ : 458.15; Found: 458.1.

Example 32

Preparation of compound 32

(2S,5R)-N-(1-(2,4-difluorophenyl)cyclobutyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9, 13,13a-Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10- Formamide

A solution of compound 32-A (22.2 mg, 0.069 mmol), compound 32-B (18.7 mg, 0.102 mmol) and HATU (43 mg, 0.113 mmol) in CH ₂ Cl ₂ (2 mL) was stirred at room temperature while adding N,N-Diisopropylethylamine (DIPEA) (0.075 mL, 0.431 mmol). After 30 minutes, the reaction mixture was diluted with ethyl acetate and washed with water (x2). After extracting the aqueous fraction with EA (x 1), the organic fractions were combined, dried, concentrated and dried in vacuo.

A mixture of the above crude product and MgBr2 (35 mg, 0.190 mmol) in MeCN ( ₂ mL) was stirred in a 50 °C bath for 1 h and cooled to 0 °C before being treated with 1 N HCl (~1 mL). The resulting solution was diluted with water and extracted with _{CH2Cl2 (} x3). The combined extracts were dried (Na ₂ SO ₄ ), and concentrated. The product was purified by preparative HPLC and lyophilized to afford compound 32. ¹ H-NMR (400MHz, CDCl ₃ ) δ10.87(s, 1H), ~9.3(br, 1H), 8.35(s, 1H), 7.50(td, J=8.7, 6.3Hz, 1H), 6.89- 6.78(m,1H),6.72(ddd,J=11.2,8.9,2.6Hz,1H),5.48-5.12(m,2H),4.72-4.60(m,1H),4.22(dd,J=13.0,4.1 Hz,1H),3.98(dd,J=12.9,9.4Hz,1H),2.68(m,4H),2.33-1.98(m,6H),1.90(m,2H),1.60(ddd,J=12.4, 4.1, 2.7Hz, 1H). ¹⁹ F-NMR (376.1 MHz, CD ₃ CN) δ -76.39 (s, 3F), -110.50 (q, J=9.2Hz, 1F), -112.65 (p, J=7.8Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value for C ₂₄ H ₂₄ F ₂ N ₃ O ₅ : 472.17; found value: 472.0.

Example 33

Preparation of compound 33

(2S,5R)-N-(1-(2,4-difluorophenyl)cyclopentyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9, 13,13a-Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10- Formamide

Compound 33 was obtained from compound 32-A and compound 33-A as described in the synthesis of compound 32. ¹ H-NMR (400MHz, CDCl ₃ ) δ10.70(s, 1H), ~9.5(br, 1H), 8.41(s, 1H), 7.43(td, J=8.9, 6.4Hz, 1H), 6.85- 6.76(m,1H),6.72(ddd,J=11.5,8.8,2.6Hz,1H),5.48-5.18(m,2H),4.68(t,J=3.2Hz,1H),4.26(dd,J= 13.0,4.1Hz,1H),4.00(dd,J＝13.0,9.4Hz,1H),2.72-2.45(m,2H),2.22-1.96(m,6H),1.96-1.75(m,5H),1.60 (ddd, J＝12.5, 4.1, 2.7Hz, 1H). ¹⁹ F-NMR (376.1MHz, CD ₃ CN) δ-76.41 (s, 3F), -107.86 (q, J＝9.4Hz, 1F), - 113.13 (p, J = 8.0 Hz, 1 F). LCMS-ESI ⁺ (m/z): [ _M +H] ⁺ _calcd for _C25H26F2N3O5 : _486.18 ; found: _485.9 .

Example 34

Preparation of compound 34

(2S,5R)-N-(1-(2,4-difluorophenyl)cyclohexyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13 ,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-methano Amide

Compound 34 was obtained from compound 32-A and compound 34-A as described in the synthesis of compound 32. ¹ H-NMR (400MHz, CDCl ₃ ) δ10.83(s, 1H), ~9.6(br, 1H), 8.44(s, 1H), 7.37(td, J=9.0, 6.4Hz, 1H), 6.97- 6.76(m,1H),6.69(ddd,J=11.9,8.8,2.7Hz,1H),5.48-5.18(m,2H),4.68(t,J=3.0Hz,1H),4.28(dd,J= 13.1,4.1Hz,1H),4.03(dd,J＝13.0,9.4Hz,1H),2.60(d,J＝13.1Hz,2H),2.29-1.96(m,4H),1.95-1.77(m,4H ), 1.77-1.65 (m, 4H), 1.61 (ddd, J=12.5, 4.1, 2.7Hz, 1H), 1.30 (br, 1H). ¹⁹ F-NMR (376.1MHz, CD ₃ CN) δ-76.41 ( s,3F),-107.86(q,J=9.4Hz,1F),-113.13(p,J=8.0Hz,1F).LCMS-ESI ⁺ (m/z):C ₂₆ H ₂₈ F ₂ N ₃ O [M+H] ⁺ theoretical value for ₅ : 500.20; found value: 500.0.

Example 35

Preparation of compound 35

(2S,5R)-N-(4-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl)-8-hydroxy-7,9-dioxo-2,3, 4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3 ]oxaazepine-10-carboxamide

Compound 35 was obtained from Compound 32-A and Compound 35-A as described in the synthesis of Compound 32. ¹ H-NMR (400MHz, CDCl ₃ ) δ10.95(s, 1H), 8.33(s, 1H), ~7.6(br, 1H), 7.38(td, J=9.0, 6.3Hz, 1H), 6.85( td,J=8.4,2.6Hz,1H),6.73(ddd,J=11.7,8.6,2.6Hz,1H),5.32(dt,J=14.4,4.0Hz,2H),4.68(t,J=3.1Hz ,1H),4.24(dd,J=13.0,3.9Hz,1H),4.11-3.81(m,5H),2.60(d,J=13.7Hz,2H),2.33-2.17(m,2H),2.18- 1.97(m,4H),1.87(m,1H),1.61(dt,J=12.5,3.3Hz,1H). ¹⁹ F-NMR(376.1MHz,CD ₃ CN)δ-76.40(s,3F),- 108.78 (q, J = 10.3, _9.8Hz , 1F), _-112.63 ( _p , J = 8.0Hz, 1F). LCMS-ESI ⁺ (m/z): _{[ M} +H] ⁺ Theoretical value: 502.18; found value: 502.0.

Example 36

Preparation of compound 36

(2S,5R)-N-((S)-1-(2,4-difluorophenyl)-2,2,2-trifluoroethyl)-8-hydroxy-7,9-dioxo- 2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b] [1,3]oxaazepine-10-carboxamide

Compound 36 was obtained from compound 32-A and compound 36-A as described in the synthesis of compound 32. ¹ H-NMR (400MHz, CDCl ₃ ) δ11.31(d, J=9.4Hz, 1H), 8.41(s, 1H), 7.65-7.44(m, 1H), 6.95(ddd, J=9.6, 5.6, 2.0Hz, 1H), 6.92-6.79(m, 1H), 6.15(h, J=7.4Hz, 1H), ~6(br, 1H), 5.41(dd, J=9.5, 4.0Hz, 1H), 5.31 (t,J=4.0Hz,1H),4.70(s,1H),4.34(dd,J=12.8,3.9Hz,1H),4.05(dd,J=12.9,9.4Hz,1H),2.26-1.99( m, 4H), 1.99-1.87 (m, 1H), 1.62 (dt, J=12.6, 3.4Hz, 1H). ¹⁹ F-NMR (376.1MHz, CDCl ₃ ) δ-75.23(t, J=6.9Hz, 3F), -76.33(s, 3F), -108.31(m, 1F), -112.30(p, J=8.0Hz , 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Theoretical for C ₂₂ H ₁₉ F ₅ N ₃ O ₅ : 500.12; Found: 500.1.

Example 37

Preparation of Compound 37

(3S,11aR)-N-(1-(2,4-difluorophenyl)cyclopropyl)-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7 ,11,11a-Hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

step 1

5-(1-(2,4-Difluorophenyl)cyclopropylcarbamoyl)-1-(2 , 2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid methyl ester (27-B, 0.150g, 0.32mmol), yellow The lid was sealed and heated to 70 °C. After 16 hours, the mixture was cooled to give 5-(1-(2,4-difluorophenyl)cyclopropylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy Crude solution of methyl-4-oxo-1,4-dihydropyridine-2-carboxylate 27-C. LCMS _- ESI ⁺ (m/z ^{): [M+H]+} _{calcd for C18H19F2N2O7 :} 439; found: 439.

Steps 2 and 3

5-(1-(2,4-difluorophenyl)cyclopropylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1, Methyl 4-dihydropyridine-2-carboxylate (27-C, 0.32 mmol, crude mixture from previous step) was dissolved in acetonitrile (1.5 mL) and acetic acid (0.2 mL). To the reaction mixture was added (S)-2-aminopropan-1-ol (0.048 g, 0.64 mmol) and K ₂ CO ₃ (0.088 g, 0.64 mmol). The reaction mixture was sealed and heated to 70 °C. After 3 hours, the reaction mixture was cooled and magnesium bromide (0.081 g, 0.44 mmol) was added. The mixture was resealed and heated to 50 °C. After 10 minutes, the reaction mixture was cooled to 0 °C, and 1N hydrochloric acid (0.5 mL) was added. Then, the reaction mixture was diluted with MeOH (2 mL). After filtration, the crude material was purified by prep-HPLC (30-70% acetonitrile:water, 0.1% TFA) to afford compound 37 as TFA salt. ¹ H-NMR (400MHz, methanol-d ₄ ) δ8.31(s, 1H), 7.62(td, J=9.2, 8.7, 6.5Hz, 1H), 7.02-6.78(m, 2H), 5.53-5.20( m, 1H), 4.68(dd, J=12.3, 4.2Hz, 1H), 4.40(dq, J=19.1, 6.7Hz, 2H), 3.98(dd, J=12.2, 10.0Hz, 1H), 3.71(dd ,J=8.3,6.3Hz,1H), 1.41(d,J=6.1Hz,3H),1.22(s,4H). ¹⁹ F-NMR (376MHz, methanol-d ₄ )δ-113.66--113.95(m ,1F),-113.94--114.29(m,1F). LCMS _- ESI ⁺ ( _m /z): [ _M +H] ⁺ _calcd for _C21H20F2N3O5 : 432.; found: 432.

Example 38

Preparation of Compound 38

(1S,4R,12aR)-N-(2,4-Difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a- Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

step 1

A solution of compound 38-A (1562 mg, 5.799 mmol) (see Example 41b in WO97/05139) in THF (10 mL) was stirred at -78 °C while adding 2.0 M LiBH ₄ , and the resulting mixture was stirred at room temperature. After 3 hours, additional 2.0M _LiBH4 in THF (3.2 mL) was added and the solution was stirred at room temperature for 17.5 hours. After diluting the reaction mixture with ethyl acetate and adding water slowly, the two phases were separated and the separated aqueous fraction was extracted with ethyl acetate (xl). The two organic fractions were washed with water ( _xl ), combined, dried ( _Na2SO4 ) and concentrated. The residue was purified by CombiFlash (40 g column) using hexane-ethyl acetate as eluent to give compound 38-B. ¹ H-NMR (400MHz, chloroform-d) δ4.11(s, 1H), 3.65-3.52(m, 2H), 3.45(m, 1H), 2.32(d, J=4.1Hz, 1H), 2.20( s, 1H), 1.75-1.64 (m, 2H), 1.61 (m, 2H), 1.49-1.41 (m, 1H), 1.47 (s, 9H), 1.28-1.23 (d, J=10Hz, 1H). LCMS-ESI ⁺ (m/z): [ _M +H] ⁺ calcd for _C12H22NO3 : _228.16 ; found: 227.7.

step 2

A solution of compound 38-B (589 mg, 2.591 mmol) and NEt ₃ (0.47 mL, 3.369 mmol) in CH ₂ Cl ₂ (6 mL) was stirred at 0° C. while MsCl (0.22 mL, 2.842 mmol) was added. After 1 hour at room temperature, the mixture was diluted with ethyl acetate and diluted with water (x2). The aqueous fraction was extracted with ethyl acetate (xl), and the organic fractions were combined, dried ( _{Na2SO4 )} and concentrated. The residue was purified by CombiFlash (40 g column) using hexane-ethyl acetate as eluent to give compound 38-C. ¹ H-NMR (400MHz, chloroform-d) δ4.39-4.28 (m, 1H), 4.16 (s, 0.4H), 4.06 (s, 0.6H), 3.98 (dd, J = 10.0, 8.7Hz, 0.6 H), 3.86(t, J=9.6Hz, 0.4H), 3.51(dd, J=9.3, 3.7Hz, 0.6H), 3.43(dd, J=9.3, 3.6Hz, 0.4H), 3.02(s, 3H), 2.59(m, 1H), 1.82-1.58(m, 4H), 1.51-1.44(m, 9H), 1.41(d, J=14.8Hz, 1H), 1.31(s, 0.6H), 1.29( s,0.4H).

step 3

To a solution of compound 38-C (769 mg, 2.518 mmol,) in DMF (5 mL) was added sodium azide (819 mg, 12.6 mmol). The reaction mixture was stirred at 50°C for 15 hours, at 80°C for 5 hours and at 100°C for 19 hours. The reaction mixture was diluted with 5% LiCl solution, and the product was extracted with ethyl acetate (x2). After washing the organic fraction with water (xl), the two organic fractions were combined, dried ( _{Na2SO4 )} and concentrated. The residue was purified by CombiFlash (40 g column) using hexane-ethyl acetate as eluent to give compound 38-D. ¹ H-NMR (400MHz, chloroform-d) δ4.16(s, 0.4H), 4.06(s, 0.6H), 3.61(dd, J=12.2, 3.6Hz, 0.6H), 3.51(dd, J= 12.1,3.2Hz,0.4H),3.38(dd,J＝9.4,3.4Hz,0.6H),3.26(dd,J＝9.8,3.3Hz,0.4H),3.06(dd,J＝12.2,9.4Hz, 0.6H), 3.01-2.92(m, 0.4H), 2.48(d, J=5.2Hz, 1H), 1.82-1.57(m, 4H), 1.46(d, J=3.0Hz, 9H), 1.42(m ,1H), 1.28(m,0.6H),1.27-1.23(m,0.4H).

step 4

To a solution of compound 38-D (507 mg, 2.009 mmol,) in ethyl acetate (10 mL) and EtOH (10 mL) was added 10% Pd/C (52 mg). The reaction mixture was stirred under _H2 atmosphere for 1.5 h. The mixture was filtered through celite, and the filtrate was concentrated to give crude compound 38-E. LCMS-ESI ⁺ (m/z): [M ₊ H] ⁺ _calcd for _C12H23N2O2 : _227.18 ; found: 226.8.

step 5

A mixture of crude compound 38-E (206 mg, 0.910 mmol), compound 38-F (330 mg, 0.953 mmol) and NaHCO ₃ (154 mg, 1.833 mmol) in water (3 mL) and EtOH (3 mL) was stirred at room temperature for 20 Hour. After the reaction mixture was diluted with water and extracted with ethyl acetate (x2), the extracts were washed with water ( _x1 ), combined, dried ( _Na2SO4 ) and concentrated to give the crude pyridine product.

The crude residue (388 mg) was dissolved in _CH2Cl2 ( ₄ mL) and 4N HCl in dioxane (4 mL). After 1.5 hours, additional 4N HCl in dioxane (4 mL) was added and stirred at room temperature for 1 hour. The mixture was dried to dryness, co-evaporated with toluene (xl) and dried in vacuo for 30 minutes.

The crude residue and 1,8-diazabicycloundec-7-ene (DBU) (1.06 mL, 7.088 mmol) in toluene (10 mL) were stirred in a 110 °C bath. After 30 minutes, the mixture was concentrated and the residue was purified by a CombiFlash 40 g column using ethyl acetate-20% MeOH/ethyl acetate as eluent to give compound 38-G. ¹ H-NMR (400MHz, chloroform-d) δ8.03(s, 1H), 7.68-7.58(m, 2H), 7.36-7.27(m, 3H), 5.53(d, J=9.9Hz, 1H), 5.11(d, J=9.9Hz, 1H), 4.93(s, 1H), 4.43-4.30(m, 2H), 3.89(dd, J=12.2, 3.3Hz, 1H), 3.73(t, J=12.0Hz ,1H),3.59(dd,J=11.9,3.3Hz,1H),2.53(d,J=2.8Hz,1H),1.87-1.67(m,4H),1.55(d,J=10.0Hz,1H) , 1.51-1.45(m, 1H), 1.38(t, J=7.1Hz, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value of C ₂₃ H ₂₅ N ₂ O ₅ : 409.18; Found: 409.2.

step 6

A mixture of compound 38-G (232 mg, 0.568 mmol) in THF (3 mL) and MeOH (3 mL) was stirred at room temperature while 1 N KOH (3 mL) was added. After 1 h, the reaction mixture was neutralized with 1N HCl (-3.1 mL), concentrated and the residue was concentrated with toluene (x3). After drying the residue in vacuo for 30 min, the crude residue, 2,4-difluorobenzylamine (86 mg, 0.601 mmol) and HATU (266 mg, 0.700 mmol) were stirred in CH ₂ Cl ₂ (4 mL) at 0 °C and DMF (4 mL) while N,N-diisopropylethylamine (DIPEA) (0.7 mL, 4.019 mmol) was added. After 45 minutes, additional 2,4-difluorobenzylamine (86 mg, 0.559 mmol), HATU (266 mg, 0.700 mmol) and N,N-diisopropylethylamine (DIPEA) (0.7 mL, 4.019 mmol). After 1.25 hours, the mixture was concentrated to remove most of _CH2Cl2 , diluted with ethyl acetate, and washed with 5% LiCl ( _x2 ). After extraction of the aqueous fraction with ethyl acetate (xl), and the organic fractions were combined, dried ( _{Na2SO4 )} and concentrated. The residue was purified by CombiFlash (40 g column) using ethyl acetate-20% MeOH/ethyl acetate as eluent to afford compound 38-H. ¹ H-NMR (400MHz, chloroform-d) δ10.48(t, J=6.0Hz, 1H), 8.33(s, 1H), 7.62-7.51(m, 2H), 7.40-7.27(m, 4H), 6.87-6.75(m,2H),5.39(d,J=10.0Hz,1H),5.15(d,J=10.0Hz,1H),4.92(s,1H),4.68-4.53(m,2H),3.97 (dd, J=12.5,3.4Hz,1H),3.77(t,J=12.2Hz,1H),3.55(dd,J=12.1,3.3Hz,1H),2.53(d,J=3.1Hz,1H) ,1.88-1.62(m,4H),1.59-1.42(m,2H) ^.19F -NMR(376MHz,chloroform-d)δ-112.17(q,J＝7.6Hz,1F),-114.79(q,J =8.6Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Theoretical for C28H26F2N3O4: 506.19; Found: 506.2.

step 7

Compound 38-H (240 mg, 0.475 mmol) was dissolved in TFA (3 mL) at room temperature for 30 min, and the solution was concentrated. The residue was purified by CombiFlash (40 _g column) using _{CH2Cl2-20 %} MeOH in _CH2Cl2 as eluent. After concentration of the collected product fractions, the residue was triturated in MeCN (-2 mL) at 0 °C for 15 min, the solid was filtered and washed with MeCN. The collected solid was dried in vacuo to afford compound 38.

The filtrate was concentrated, and the residue was dissolved in MeCN (-1 mL) and water (-1 mL) by heating. The solution was cooled slowly to room temperature, then cooled in an ice bath for 15 minutes. The solid was filtered and washed with MeCN and dried in vacuo to afford additional compound 38. ¹ H-NMR (400MHz, chloroform-d) δ11.68(s,1H),10.42(s,1H),8.27(s,1H),7.41-7.31(m,1H),6.86-6.73(m,2H ),4.90(d,J=2.5Hz,1H),4.71-4.53(m,2H),4.07(d,J=10.6Hz,1H),3.90-3.67(m,2H),2.68(s,1H) ,2.01(s,1H),1.97-1.80(m,3H),1.80-1.62(m,2H). ¹⁹ F-NMR(376MHz,chloroform-d)δ-112.28(m,1F),-114.74(m , 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Theoretical for C ₂₁ H ₁₉ F ₂ N ₃ O ₄ : 416.14; Found: 416.3.

Examples 39 and 40

Preparation of Compounds 39 and 40

(2R,3S,5R,13aS)-N-(2,4-Difluorobenzyl)-8-hydroxy-3-methyl-7,9-dioxo-2,3,4,5,7 ,9,13,13a-Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine -10-carboxamide 39 and (2S,3R,5S,13aR)-N-(2,4-difluorobenzyl)-8-hydroxy-3-methyl-7,9-dioxo-2, 3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1 ,3] Oxaazepine-10-carboxamide 40

step 1

Cuprous cyanide (290 mg, 3.27 mmol) was suspended in 3.3 mL THF and cooled to -78 °C. A 1.6M solution of MeLi (4.1 mL, 6.56 mmol) in diethyl ether was added dropwise and the reaction solution was allowed to warm to room temperature over a period of 2 hours and then cooled to -78 °C. (1R,3R,5S)-tert-butyl 6-oxobicyclo[3.1.0]hexane-3-ylcarbamate (330 mg, 1.66 mmol) in 3.3 mL of THF was added dropwise, followed by trifluorinated Boron diethyl etherate (0.25 mL, 1.99 mmol), allowed to warm to -30°C over 30 minutes and stirred between -35°C and -25°C for 1 hour. Then, the reaction solution was warmed to room temperature and quenched with a saturated mixture of _NH3 (aq)/ _NH4 (aq), extracted with EtOAc, washed with brine, dried over _MgSO4 , filtered, concentrated, and passed through SGC ( 0-10% EtOH/DCM) to give racemic tert-butyl (1S,3S,4S)-3-hydroxy-4-methylcyclopentylcarbamate. ¹ H-NMR (400MHz, chloroform-d) δ5.16(s, 1H), 3.98(s, 1H), 3.74(q, J=4.3Hz, 1H), 3.65(q, J=7.0Hz, 1H) ,2.23(dt,J=14.0,7.0Hz,1H),1.98(dt,J=13.3,7.0Hz,1H),1.89-1.79(m,1H),1.58-1.44(m,1H),1.38(s , 9H), 1.18 (t, J=7.0Hz, 1H), 0.91 (d, J=7.0Hz, 3H).

step 2

3 mL of HCl/dioxane (4M, 12 mmol) was added to racemic tert-butyl (1S,3S,4S)-3-hydroxy-4-methylcyclopentylcarbamate (182mg, 0.85mmol) in solution. The reaction mixture was stirred at room temperature for 2 hours, concentrated and chased twice with toluene to give racemic (1S,2S,4S)-4-amino-2-methylcyclopentanol.

step 3

5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine- Methyl 2-carboxylate (1-C, 310 mg, 0.75 mmol), racemic (1S, 2S, 4S)-4-amino-2-methylcyclopentanol (115 mg, 0.76 mmol) and potassium carbonate ( 232 mg, 1.68 mmol) were dissolved in 3.8 mL of acetonitrile/0.2 mL acetic acid and stirred at 90 °C for 2 hours, after which the reaction mixture was partitioned between DCM and brine, the aqueous phase was extracted into DCM, dried _over MgSO and combined The organic phase was filtered, concentrated and purified by SGC (0-10% EtOH/DCM) to afford Intermediate 39-A.

step 4

Intermediate 39-A (190 mg) was separated on a Lux Cellulose-2 column by chiral prep-HPLC using 9:1 ACN:MeOH as eluent to give intermediate 39-B in enantiomerically enriched form (first eluting peak) and 40-A (second eluting peak). For intermediate 39-B: (absolute stereochemistry confirmed by XRay crystallography), chiral HPLC retention time = 3.98 min (Lux Cellulose-2IC, 150 x 4.6 mm, 2 mL/min 9:1 ACN:MeOH). For intermediate 40-A: (absolute stereochemistry confirmed by XRay crystallography), chiral HPLC retention time = 6.35 min (Lux Cellulose-2IC, 150 x 4.6 mm, 2 mL/min 9:1 ACN:MeOH).

Step 5a

Magnesium bromide (68 mg, 0.37 mmol) was added to a solution of Intermediate 39-B (83 mg, 0.18 mmol) in 2 mL of acetonitrile. The reaction mixture was stirred at 50°C for 1 hour, acidified with 10% aqueous HCl, partitioned between aqueous and dichloromethane, and the aqueous phase was extracted into dichloromethane. The combined organic phases were dried over MgSO ₄ , filtered, concentrated, and purified by silica gel chromatography (0-10% EtOH/DCM) to afford compound 39. ¹ H-NMR (400MHz, chloroform-d) δ12.32(s,1H),10.36(s,1H),8.29(s,1H),7.44-7.33(m,1H),6.88-6.76(m,2H ), 5.37(dd, J=9.5, 4.1Hz, 1H), 5.28(t, J=5.3Hz, 1H), 4.63(d, J=5.9Hz, 2H), 4.23(d, J=23.0Hz, 2H ),3.99(dd,J=12.7,9.5Hz,1H),3.72(q,J=7.0Hz,1H),2.51(dq,J=13.7,6.8,6.1Hz,1H),2.15(ddd,J= 14.7,8.3,2.3Hz,1H),1.94(d,J=12.7Hz,1H),1.77(ddd,J=12.7,4.0,2.9Hz,1H),1.61(dt,J=14.6,5.2Hz,2H ), 1.24 (t, J=7.0Hz, 1H), 1.09(d, J=7.2Hz, 3H). LCMS _- ESI ⁺ (m/z): [ _M +H] ⁺ _calcd for _C22H22F2N3O5 : _446.15 ; found: 446.2.

Step 5b

Magnesium bromide (59 mg, 0.32 mmol) was added to a solution of Intermediate 40-A (70 mg, 0.15 mmol) in 2 mL of acetonitrile. The reaction mixture was stirred at 50°C for 1 hour, acidified with 10% aqueous HCl, partitioned between aqueous and dichloromethane, and the aqueous phase was extracted into dichloromethane. The combined organic phases were dried over MgSO ₄ , filtered, concentrated, and purified by silica gel chromatography (0-10% EtOH/DCM) to afford compound 40. ¹ H-NMR (400MHz, chloroform-d) δ12.32(s,1H),10.36(s,1H),8.29(s,1H),7.44-7.33(m,1H),6.88-6.76(m,2H ), 5.37(dd, J=9.5, 4.1Hz, 1H), 5.28(t, J=5.3Hz, 1H), 4.63(d, J=5.9Hz, 2H), 4.23(d, J=23.0Hz, 2H ),3.99(dd,J=12.7,9.5Hz,1H),3.72(q,J=7.0Hz,1H),2.51(dq,J=13.7,6.8,6.1Hz,1H),2.15(ddd,J= 14.7,8.3,2.3Hz,1H),1.94(d,J=12.7Hz,1H),1.77(ddd,J=12.7,4.0,2.9Hz,1H),1.61(dt,J=14.6,5.2Hz,2H ), 1.24 (t, J=7.0Hz, 1H), 1.09(d, J=7.2Hz, 3H). LCMS _- ESI ⁺ (m/z): [ _M +H] ⁺ _calcd for _C22H22F2N3O5 : _446.15 ; found: 446.2.

Example 41

Preparation of Compound 41

(1R,4S,12aR)-7-Hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12, 12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

step 1

A solution of 41-A (2020 mg, 7.463 mmol) (prepared by the same method as 38-A) in THF (14 mL) was stirred at 0 °C while adding 2.0 M LiBH in THF (7.5 mL, 15 mmol) ₄ . After stirring the resulting mixture at room temperature for 21 h, it was cooled at 0 °C and diluted with EA, then quenched by the slow addition of water. After separation of the two phases, the aqueous fraction was extracted with EA (xl), and the two organic fractions were washed with water (xl), combined, dried ( _{Na2SO4 )} and concentrated. The residue was purified by CombiFlash (120 g column) using hexane-EA as eluent to afford 41-B. LCMS-ESI ⁺ (m/z): [ _{MC4H8 +} H] ⁺ _calcd for _C8H14NO3 : _172.10 ; found: 171.95.

step 2

A 100-mL round bottom flask was charged with reactant 41-B (1.6 g, 7.05 mmol) and triethylamine (0.94 g, 9.3 mmol) in DCM (20 mL). Methanesulfonyl chloride (0.91 g, 8.0 mmol) was added to the reaction mixture. Then, the reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with EA (100 mL) and washed with water (2x). The aqueous fraction was extracted with EA (1x), the organic fractions were combined, dried ( _{Na2SO4 )} and concentrated. Purification of the residue by CombiFlash (120 g column, cartridge used) using hexane-EA as eluent afforded 41-C. LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical: _{C18H19F2N2O7 : 306 ;} found: ₃₀₆ .

step 3

A 100-mL round bottom flask was charged with reactant 41-C (2.1 g, 6.9 mmol) and sodium azide (2.3 g, 34.5 mmol) in DMF (10 mL). Then, the reaction mixture was stirred overnight at 100°C. The mixture was diluted with EA (100 mL) and washed with water (2x). The aqueous fraction was extracted with EA (1x), and the organic fractions were combined, dried ( _{Na2SO4 )} and concentrated. The residue was purified by CombiFlash (120 g column, cartridge used) using hexane-EA as eluent to afford 41-D. LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value for C ₁₈ H ₁₉ F ₂ N ₂ O ₇ : 253; found value: 253.

step 4

To a solution of reactant 41-D (1.3 g) in EA (20 mL) and EtOH (20 mL) purged with _N2 was added Pd/C (130 mg). The mixture was stirred under _H2 for 3 h. The mixture was filtered through celite and the filtrate was concentrated to afford compound 41-E. LCMS _- ESI ⁺ (m/z ^{): [M+H]+} _{calcd for C18H19F2N2O7 :} 227; found: 227.

step 5

A 100-mL round bottom flask was charged with 41-E (1.05 g, 4.62 mmol) and reactant 38-F (1.6 g, 4.62 mmol) in ethanol (20 mL). Sodium bicarbonate (0.77 g, 9.2 mmol) in water (20 mL) was added to the reaction mixture. Then, the reaction mixture was stirred overnight at room temperature. The mixture was diluted with EA (100 mL) and washed with water (2x). The aqueous fraction was extracted with EA (1x), and the organic fractions were combined, dried ( _{Na2SO4 )} and concentrated. The crude product (2.4 g) was used in the next step without further purification. LCMS _- ESI ⁺ (m/z ^{): [M+H]+} _{calcd for C18H19F2N2O7 :} 556; found: 556.

A 100-mL round bottom flask was charged with the crude product from the previous reaction in 4N HCl/dioxane (24.7 mL). Then, the reaction mixture was stirred at room temperature for 1 hour. After concentration, the intermediate (2.1 g) and DBU (3.27 g, 21.5 mmol) in toluene (30 mL) were heated to 110 °C while stirring for 1 hour. After concentration, the residue was purified by CombiFlash (120 g column) using hexane-ethyl acetate as eluent to afford 41-F. LCMS _- ESI ⁺ (m/z ^{): [M+H]+} _{calcd for C18H19F2N2O7 :} 409; found: 409.

step 6

A 100-mL round bottom flask was charged with reactant 41-F (0.5 g, 1.22 mmol) in THF (5 mL) and MeOH (5 mL). 1 N KOH (3.7 mL) was added to the reaction mixture. Then, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified by addition of 1 N HCl (3.7 mL), concentrated to remove most of the organic solvent, and extracted with EtOAc (2X). The organic layers were combined, dried (Na ₂ SO ₄ ) and concentrated to afford compound 41-G.

step 7

A 100-mL round bottom flask was charged with reactant 41-G (0.14 g, 0.37 mmol), (2,4,6-trifluorophenyl)methanamine (0.12 g, 0.73mmol), N,N-diisopropylethylamine (DIPEA) (0.24g, 1.84mmol) and HATU (0.28g, 0.74mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EA (100 mL), washed with sat. NaHCO ₃ (2x), sat. NH ₄ Cl (2x), and dried over Na ₂ SO ₄ . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to afford compound 41-H. LCMS-ESI ⁺ (m/z): [M ₊ H] ⁺ _calcd for _C18H19F2N2O7 : _524.5 ; found: _524.5 .

Step 8

A 50-mL round bottom flask was charged with reactant 41-H (0.13 g, 0.25 mmol) in TFA (2 mL). The reaction mixture was stirred for 30 minutes at room temperature. After concentration, the crude material was purified by column chromatography on silica gel with EtOAc-MeOH to give compound 41. ¹ H-NMR (400MHz, chloroform-d) δ11.61(s, 1H), 10.70-10.01(m, 1H), 8.26(s, 1H), 6.65(t, J=8.1Hz, 2H), 4.88( s,1H),4.65(dd,J=6.1,2.4Hz,2H),4.07(d,J=10.9Hz,1H),3.93-3.58(m,2H),2.67(d,J=3.1Hz,1H ), 2.08-1.41 (m, 7H). ¹⁹ F-NMR (376MHz, chloroform-d) δ-109.22 (d, J=11.6Hz, 1F), -111.04--112.79 (m, 2F). LCMS _- ESI ⁺ ( _m /z): [ _M +H] ⁺ _calcd for _C21H20F2N3O5 : 434.; found: 434.

Example 42

Preparation of Compound 42

(2R,5S,13aR)-8-Hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13, 13a-Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

step 1

1-(2,2-Dimethoxyethyl)-5-methoxy-6-(methoxy Carbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (3.15g, 10mmol), and placed in a bath at 75°C. The reaction mixture was stirred for 7 hours, cooled and stored at -10°C for 3 days, and heated to 75°C for an additional 2 hours. The material was cooled and carried on to the next step as crude material.

step 2

The crude reaction mixture from Step 1 (20 mL, 4.9 mmol) was transferred to a flask containing (1R,3S)-3-aminocyclopentanol (0.809 g, 8 mmol). The mixture was diluted with acetonitrile (16.8 mL), treated with potassium carbonate (0.553 g, 4 mmol), and heated to 85 °C. After 2 hours, the reaction mixture was cooled to ambient temperature and stirred overnight. 0.2M HCl (50 mL) was added and the clear yellow solution was extracted with dichloromethane (2x150 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to 1.49 g of a pale orange solid. Recrystallization from dichloromethane:hexanes gave the desired intermediate 42A: LCMS-ESI ⁺ (m/z): _[ M ₊ H] ⁺ Theoretical for _C15H17N2O6 : _321.11 ; found: 321.3.

step 3

Intermediate 42-A (0.225g, 0.702mmol) and (2,4,6-trifluorophenyl)methanamine (0.125g, 0.773mmol) were suspended in acetonitrile (4mL) and washed with N,N-diiso Treated with propylethylamine (DIPEA) (0.183 mmol, 1.05 mmol). To this suspension was added (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene Methaniminium hexafluorophosphate (HATU, 0.294 g, 0.774 mmol). After 1.5 hours, the crude reaction mixture was carried on to the next step. LCMS _- ESI ⁺ (m/z): _{[ M} +H] ⁺ Calc: _C22H21F3N3O5 : _464.14 ; Found: 464.2.

step 4

To the crude reaction mixture from the previous step was added MgBr2 (0.258 _g , 1.40 mmol). The reaction mixture was stirred at 50°C for 10 minutes, acidified with 10% aqueous HCl and extracted twice with dichloromethane. The combined organic phases were dried over MgSO ₄ , filtered, concentrated and purified by silica gel chromatography (EtOH/dichloromethane) followed by HPLC (ACN/H ₂ O with 0.1% TFA modifier) to give compound 42: ¹ H-NMR(400MHz,DMSO-d ₆ )δ12.43(s,1H),10.34(t,J=5.7Hz,1H),8.42(s,1H),7.19(t,J=8.7Hz,2H) ,5.43(dd,J=9.5,4.1Hz,1H),5.08(s,1H),4.66(dd,J=12.9,4.0Hz,1H),4.59(s,1H),4.56-4.45(m,2H ), 4.01 (dd, J = 12.7, 9.7Hz, 1H), 1.93 (s, 4H), 1.83 (d, J = 12.0Hz, 1H), 1.56 (dt, J = 12.0, 3.4Hz, 1H). LCMS _- ESI ⁺ (m/z): [ _M +H] ⁺ calcd for _C21H19F3N3O5 : _450.13 ; found: _450.2 .

Example 43

Preparation of Compound 43

(12aR)-N-((R)-1-(2,4-difluorophenyl)ethyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8 ,12,12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

step 1

A 100-mL round bottom flask was charged with reactants 41-G (0.14 g, 0.37 mmol), (R)-1-(2,4-difluorophenyl) ethylamine (0.12 g, 0.74 mmol), N,N-Diisopropylethylamine (0.24 g, 1.84 mmol) and HATU (0.28 g, 0.74 mmol) were dissolved in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EA (100 mL), washed with saturated NaHCO ₃ (2x), saturated NH ₄ Cl (2x), and dried over Na ₂ SO ₄ . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to give compound 43-A. LCMS _- ESI ⁺ (m/z ^{): [M+H]+} _{calcd for C18H19F2N2O7 :} 520; found: 520.

step 2

A 50-mL round bottom flask was charged with reactant 43-A (0.14 g, 0.27 mmol) in TFA (2 mL). The reaction mixture was stirred for 30 minutes at room temperature. After concentration, the crude material was purified by column chromatography on silica gel with EtOAc-MeOH to afford compound 43. ¹ H-NMR (400MHz, chloroform-d) δ11.65(s,1H),10.57(s,1H),8.22(s,1H),7.31(m,1H),6.99-6.62(m,2H), 5.64-5.32(m,1H),4.90(d,J=2.7Hz,1H),4.04(d,J=11.5Hz,1H),3.93-3.63(m,2H),2.67(s,1H),2.08 -1.40(m,9H). ¹⁹ F-NMR (376 MHz, chloroform-d) δ-113.09 (m, 1F), -115.01 (m, 1F). LCMS _- ESI ⁺ ( _m /z): [ _M +H] ⁺ _calcd for _C21H20F2N3O5 : 430.; found: 430.

Example 44

Preparation of Compound 44

(13aS)-8-Hydroxy-7,9-dioxo-N-(2,3,4-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro -2,5-Methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

step 1

Compound 15-B (40mg, 0.12mmol) was dissolved in 1mL of acetonitrile, and 2,3,4-trifluorobenzylamine (29mg, 0.18mmol), HATU (53mg, 0.14mmol), N,N- Diisopropylethylamine (DIPEA) (20 mg, 0.16 mmol) was treated and stirred at room temperature for 2 hours, after which LCMS analysis showed complete consumption of compound 15-B and formation of intermediate 44-A. The reaction mixture was carried on to the next step.

step 2

To the crude reaction solution from the previous step was added MgBr2 (63 _mg , 0.34 mmol). The reaction mixture was stirred at 50°C for 1 hour, acidified with 10% aqueous HCl, partitioned between aqueous and dichloromethane, and the aqueous phase was extracted into dichloromethane. The combined organic phases were dried over MgSO ₄ , filtered, concentrated and purified by HPLC (ACN/H ₂ O with 0.1% TFA modifier) to afford compound 44. ¹ H-NMR (400MHz, DMSO-d ₆ ) δ12.45(s, 1H), 10.38(t, J=6.0Hz, 1H), 8.43(s, 1H), 7.27(q, J=9.2Hz, 1H ), 7.16(q, J=8.5Hz, 1H), 5.42(dd, J=9.5, 4.0Hz, 1H), 5.08(s, 1H), 4.76-4.47(m, 4H), 4.01(dd, J= 12.8, 9.7Hz, 1H), 1.92(s, 4H), 1.82(d, J=12.1Hz, 1H), 1.55(dt, J=12.2, 2.9Hz, 1H). LCMS _- ESI ⁺ (m/z): [ _M +H] ⁺ calcd for _C21H19F3N3O5 : _450.13 ; found: _450.2 .

Example 45

Preparation of Compound 45

(13aS)-8-Hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro -2,5-Methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

step 1

Compound 15-B (38mg, 0.12mmol) was dissolved in 1mL of acetonitrile, with 2,4,6-trifluorobenzylamine (34mg, 0.21mmol), HATU (50mg, 0.13mmol), N,N- Diisopropylethylamine (DIPEA) (23 mg, 0.18 mmol) was treated and stirred at room temperature for 2 hours, after which LCMS analysis showed complete consumption of compound 15-B and formation of intermediate 45-A. The reaction mixture was carried on to the next step.

step 2

To the crude reaction solution from the previous step was added MgBr2 (55 _mg , 0.30 mmol). The reaction mixture was stirred at 50°C for 1 hour, acidified with 10% aqueous HCl, partitioned between the aqueous solution and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO ₄ , filtered, concentrated and purified by HPLC (ACN/H ₂ O with 0.1% TFA modifier) to afford compound 45. ¹ H-NMR (400MHz,DMSO-d ₆ )δ12.37(s,1H),10.37-10.25(m,1H),8.37(s,1H),7.14(t,J＝8.7Hz,2H),5.37 (dd,J=9.5,4.0Hz,1H),5.02(s,1H),4.66-4.40(m,4H),3.95(dd,J=12.8,9.6Hz,1H),1.87(s,4H), 1.77 (d, J = 11.9 Hz, 1H), 1.50 (dt, J = 11.8, 3.2 Hz, 1 H). LCMS _- ESI ⁺ (m/z): [ _M +H] ⁺ calcd for _C21H19F3N3O5 : _450.13 ; found: _450.2 .

Example 46

Preparation of compound 46

(13aS)-N-(2,6-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2 ,5-Methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

step 1

Compound 15-B (38mg, 0.12mmol) was dissolved in 1mL of acetonitrile, with 2,6-difluorobenzylamine (19mg, 0.14mmol), HATU (56mg, 0.15mmol), N,N-diisopropyl DIPEA (20 mg, 0.15 mmol) and stirred at room temperature for 90 min, after which LCMS analysis showed complete consumption of compound A and formation of intermediate 46-A. The reaction mixture was carried on to the next step.

step 2

To the crude reaction solution from the previous step was added MgBr2 (50 _mg , 0.27 mmol). The reaction mixture was stirred at 50°C for 1 hour, acidified with 10% aqueous HCl, partitioned between the aqueous solution and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO ₄ , filtered, concentrated and purified by HPLC (ACN/H ₂ O with 0.1% TFA modifier) to afford compound 46. ¹ H-NMR (400MHz,DMSO-d ₆ )δ12.37(s,1H),10.33-10.26(m,1H),8.37(s,1H),7.39-7.29(m,1H),7.05(t, J＝7.9Hz, 2H), 5.37(dd, J＝9.5, 4.1Hz, 1H), 5.02(s, 1H), 4.66-4.45(m, 4H), 3.95(dd, J＝12.7, 9.6Hz, 1H ), 1.87 (s, 4H), 1.77 (d, J=12.0Hz, 1H), 1.50 (dt, J=12.2, 3.5Hz, 1H). LCMS _- ESI ⁺ (m/z): [ _M +H] ⁺ _calcd for _C21H20F2N3O5 : _432.14 ; found: 432.2.

Example 47

Preparation of compound 47

(1R,4S,12aR)-N-(2,4-Difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a- Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

step 1

Crude acid 41-G (0.45g, 1.18mmol), 2,4-difluorobenzylamine (0.35g, 2.44mmol), N,N-diisopropylethylamine (DIPEA) (0.79g, 6.11 mmol) and HATU (0.93 g, 2.44 mmol) were dissolved in DCM (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EA (100 mL), washed with sat. NaHCO ₃ (2x), sat. NH ₄ Cl (2x), and dried over Na ₂ SO ₄ . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to give compound 47-A. LCMS _- ESI ⁺ (m/z ^{): [M+H]+} _{calcd for C18H19F2N2O7 :} 506; found: 506.

step 2

A 50-mL round bottom flask was charged with reactant 47-A (0.5 g, 0.99 mmol) in TFA (6 mL). The reaction mixture was stirred for 30 minutes at room temperature. After concentration, the crude material was purified by column chromatography on silica gel with EtOAc-MeOH to give compound 47. ¹ H NMR (400MHz, chloroform-d) δ11.70(s,1H),10.44(s,1H),8.29(s,1H),7.60-7.29(m,1H),6.95-6.58(m,2H) ,4.10(s,1H),4.02-3.54(m,3H),2.68(d,J＝3.1Hz,1H),2.00-1.40(m,8H). ¹⁹ F NMR(376MHz,chloroform-d)δ- 112.31 (d, J = 8.0Hz, 1F), -114.77 (d, J = 8.4Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H of C ₂₁ H ₂₀ F ₂ N ₃ O ₅ ] ⁺ Theoretical value: 416.; Measured value: 416.

Example 48

Preparation of Compound 48

(1S,4R,12aS)-N-(2,4-Difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a- Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

48-B was prepared analogously to 55-H in Example 55, substituting 48-A for 55-A. Compound 48 was prepared as described for compound 38 in Example 38, substituting 48-B for 38-B to afford compound 48. ¹ H-NMR (400MHz, chloroform-d) δ11.79(s,1H),10.44(m,1H),8.33(s,1H),7.42-7.31(m,1H),6.86-6.74(m,2H ),4.74(s,1H),4.63(d,J＝5.8Hz,2H),4.19(m,1H),4.07-4.03(m,2H),2.83(s,1H),1.92-1.68(m, 6H). ¹⁹ F NMR (376MHz, chloroform-d) δ-112.3 (m, 1F), -114.8 (m, 1F). LCMS-ESI ⁺ (m/z): [M of C ₂₁ H ₂₀ F ₂ N ₃ O ₄ +H] ⁺ Theoretical value: 416.14.; Measured value: 416.07.

Example 49

Preparation of Compound 49

(2S,5R,13aS)-8-Hydroxy-7,9-dioxo-N-((3-(trifluoromethyl)pyridin-2-yl)methyl)-2,3,4,5, 7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine Hetero-10-carboxamide

step 1

Compound 15-B (44 mg, 0.11 mmol) was dissolved in 1 mL of acetonitrile, and (3-(trifluoromethyl)pyridin-2-yl)methanamine (38 mg, 0.18 mmol, HCl salt), HATU (69 mg, 0.18mmol), N,N-diisopropylethylamine (DIPEA) (0.07mL, 0.40mmol), and stirred at room temperature for 1 hour, after which LCMS analysis showed that compound 15-B was completely consumed and intermediate 49- A formed. The reaction mixture was carried on to the next step.

step 2

To the crude reaction solution from the previous step was added MgBr2 (51 _mg , 0.28 mmol). The reaction mixture was stirred at 50° C. for 90 minutes, acidified with 10% aqueous HCl, partitioned between the aqueous solution and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO ₄ , filtered, concentrated, and triturated with methanol followed by diethyl ether to afford compound 49. ¹ H-NMR(400MHz,DMSO-d ₆ )δ12.42(s,1H),10.80-10.70(m,1H),8.83(d,J=5.0Hz,1H),8.44(s,1H),8.19 (d,J=8.6Hz,1H),7.56(dd,J=7.7,5.2Hz,1H),5.43(dd,J=9.5,4.0Hz,1H),5.08(s,1H),4.86-4.80( m,2H),4.67(dd,J=12.9,4.0Hz,1H),4.59(s,1H),4.02(dd,J=12.6,9.8Hz,1H),1.93(s,4H),1.82(d , J=12.1Hz, 1H), 1.60-1.52 (m, 1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value for C ₂₁ H ₂₀ F ₃ N ₄ O ₅ : 465.14; found value: 465.2.

Examples 50 and 51

Preparation of Compounds 50 and 51

N-(2,4-difluorobenzyl)-9-hydroxy-8,10-dioxo-2,3,5,6,8,10,14,14a-octahydro-2,6-bridge Methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,6,3]dioxazocine-11-carboxamide 50 and 51

step 1

5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine- 2-Carboxylic acid methyl ester (1-C, 392 mg, 0.95 mmol) (Example 87), racemic cis-5-aminotetrahydro-2H-pyran-3 alcohol (WO 2012/145569 Bennett, BL et al. , submitted on April 20, 2012) (112mg, 0.95mmol) and potassium carbonate (134mg, 0.97mmol) were dissolved in 3.8mL acetonitrile/0.2mL acetic acid and stirred at 90°C for 90 minutes, after which the reaction mixture was Partitioned between DCM and brine, the aqueous phase was extracted with DCM, the combined organic phases were dried over MgSO ₄ , filtered, concentrated and purified by SGC (0-10% EtOH/DCM) to afford Intermediate 50-A.

step 2

Intermediate 50-A (40 mg) was isolated by chiral SFC on a Chiralpak IC column using 10% DMF in supercritical carbon dioxide as eluent to give the intermediate in enantiomerically enriched form 50-B (first eluting peak) and 51-A (second eluting peak). For intermediate 50-B: (absolute stereochemistry unknown), chiral HPLC retention time = 11.48 min (Chiralpak IC, 150 x 4.6 mm, 1 mL/min MeOH). For intermediate 51-A: ((absolute stereochemistry unknown), chiral HPLC retention time = 14.35 min (Chiralpak IC, 150 x 4.6 mm, 1 mL/min MeOH).

Step 3a

Magnesium bromide (12 mg, 0.06 mmol) was added to a solution of Intermediate 50-B (10.5 mg, 0.02 mmol, absolute stereochemistry unknown) in 1 mL of acetonitrile. The reaction mixture was stirred at 50°C for 1 hour, acidified with 10% aqueous HCl, partitioned between the aqueous solution and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO ₄ , filtered, concentrated and purified by HPLC (ACN/H ₂ O with 0.1% TFA modifier) to afford compound 50. ¹ H-NMR (400MHz, chloroform-d) δ10.47(t, J=5.8Hz, 1H), 8.42(s, 1H), 7.35(q, J=8.6, 8.2Hz, 1H), 6.81(q, J=8.7,8.0Hz,2H),6.41(dd,J=10.0,3.6Hz,1H),4.79(s,1H),4.65(s,2H),4.36-4.26(m,2H),4.20-4.08 (m,2H),3.98(dd,J=12.4,10.2Hz,1H),3.88(t,J=11.8Hz,2H),2.27(dt,J=13.3,3.1Hz,1H),2.15-2.06( m, 1H). LCMS-ESI ⁺ (m/z): _{[ M} +H] ⁺ _calcd for _C21H20F2N3O6 : _448.40 ; found: 448.2.

Step 3b

Magnesium bromide (13 mg, 0.07 mmol) was added to a solution of Intermediate 51-A (13.2 mg, 0.03 mmol, absolute stereochemistry unknown) in 1 mL of acetonitrile. The reaction mixture was stirred at 50°C for 1 hour, acidified with 10% aqueous HCl, partitioned between the aqueous solution and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO ₄ , filtered, concentrated and purified by HPLC (ACN/H ₂ O with 0.1% TFA modifier) to give compound 51. ¹ H-NMR (400MHz, chloroform-d) δ10.47(t, J=5.8Hz, 1H), 8.42(s, 1H), 7.35(q, J=8.6, 8.2Hz, 1H), 6.81(q, J=8.7,8.0Hz,2H),6.41(dd,J=10.0,3.6Hz,1H),4.79(s,1H),4.65(s,2H),4.36-4.26(m,2H),4.20-4.08 (m,2H),3.98(dd,J=12.4,10.2Hz,1H),3.88(t,J=11.8Hz,2H),2.27(dt,J=13.3,3.1Hz,1H),2.15-2.06( m, 1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value for C ₂₁ H ₂₀ F ₂ N ₃ O ₆ : 448.40; found value: 448.2.

Example 52

Preparation of compound 52

(2S,5R,13aS)-N-(2-Cyclopropoxy-4-fluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9, 13,13a-Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10- Formamide

step 1

A solution of cyclopropanol (1.9 g, 29 mmol) in 20 mL of dioxane was added dropwise to a solution of sodium hydride (60% dispersion in mineral oil, 1.04 g, 26 mmol) in 80 mL of dioxane at 0 °C middle. The reaction mixture was allowed to warm to room temperature, 2,4-difluorobenzonitrile (3.48 g, 25 mmol) was added in portions, and the reaction temperature was raised to 95°C. After stirring for 18 hours, the reaction solution was cooled to room temperature, diluted with ethyl acetate, washed twice with water and twice with brine, dried over MgSO ₄ , filtered and concentrated on silica gel. Purification by silica gel chromatography (0-10% EtOAc/hexanes) afforded 2-cyclopropoxy-4-fluorobenzonitrile. ¹ H-NMR (400MHz, chloroform-d) δ7.52 (dd, J = 8.6, 6.2Hz, 1H), 7.05 (dd, J = 10.5, 2.3Hz, 1H), 6.73 (td, J = 8.2, 2.3 Hz, 1H), 3.87-3.76(m, 1H), 0.87(m, 4H).

step 2

To a suspension of lithium aluminum hydride in THF (1M, 15 mL, 15 mmol) at 0 °C was added dropwise 2-cyclopropoxy-4-fluorobenzonitrile in 14 mL of diethyl ether. The reaction solution was stirred for 3 hours, gradually warmed to room temperature, at which time it was recooled to 0 °C, an additional 8 mL of lithium aluminum hydride in THF (1 M, 8 mmol) was added, and stirred for an additional 90 minutes. The reaction was quenched by successive additions of 0.9 mL of water, 0.9 mL of 15% NaOH _(aq) and 2.7 mL of water. The reaction was filtered through celite, rinsed with ether, dried over _MgSO4 , and concentrated to give 2-cyclopropoxy-4-fluorobenzylamine of sufficient purity to proceed as crude material. ¹ H-NMR (400MHz, chloroform-d) δ7.17-7.08 (m, 1H), 6.96 (dd, J = 10.9, 2.4Hz, 1H), 6.61 (td, J = 8.3, 2.5Hz, 1H), 3.78-3.66(m,3H),0.89-0.72(m,4H).

step 3

Compound 15-B (46 mg, 0.14 mmol) was dissolved in 1 mL of acetonitrile, and was treated with 2-cyclopropoxy-4-fluorobenzylamine (32 mg, 0.18 mmol), HATU (62 mg, 0.16 mmol), N, N-diisopropylethylamine (DIPEA) (0.04 mL, 0.22 mmol) was treated and stirred at room temperature for 2 hours, after which LCMS analysis showed complete consumption of compound 15-B and formation of intermediate 52-A. The reaction mixture was carried on to the next step.

step 4

To the crude reaction solution from the previous step was added MgBr2 (56 _mg , 0.30 mmol). The reaction mixture was stirred at 50°C for 90 minutes, acidified with 10% aqueous HCl, partitioned between the aqueous solution and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO ₄ , filtered, concentrated and purified by HPLC (ACN/H ₂ O with 0.1% TFA modifier) to afford compound 52. ¹ H-NMR (400MHz, DMSO-d ₆ ) δ12.44(s, 1H), 10.21(t, J=5.8Hz, 1H), 8.41(s, 1H), 7.22-7.15(m, 1H), 7.12 (dd,J=11.2,2.5Hz,1H),6.72(td,J=8.5,2.5Hz,1H),5.42(dd,J=9.6,4.1Hz,1H),5.07(s,1H),4.66( dd,J=12.8,4.1Hz,1H),4.58(s,1H),4.34(dd,J=5.6,2.4Hz,2H),4.04-3.91(m,2H),1.92(s,4H),1.82 (d,J=11.9Hz,1H),1.55(dt,J=12.4,3.5Hz,1H),0.80(q,J=6.3,5.7Hz,2H),0.72(q,J=6.0,4.9Hz, 2H). LCMS-ESI ⁺ (m/z): [ _M +H] ⁺ calcd for _C24H25FN3O6 : _{470.17 ;} found: 470.1.

Example 53

Preparation of compound 53

(2R,5S,13aR)-N-(2-cyclopropoxy-4-fluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9, 13,13a-Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10- Formamide

step 1

Compound 42-A (46mg, 0.14mmol) was dissolved in 1mL of acetonitrile and washed with 2-cyclopropoxy-4-fluorobenzylamine (33mg, 0.18mmol), HATU (61mg, 0.16mmol), N, N-diisopropylethylamine (DIPEA) (0.04 mL, 0.24 mmol) was treated and stirred at room temperature for 2 hours, after which LCMS analysis showed complete consumption of compound 42-A and formation of intermediate 53-A. The reaction mixture was carried on to the next step.

step 2

To the crude reaction solution from the previous step was added MgBr2 (55 _mg , 0.30 mmol). The reaction mixture was stirred at 50°C for 90 minutes, acidified with 10% aqueous HCl, partitioned between the aqueous solution and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO ₄ , filtered, concentrated and purified by HPLC (ACN/H ₂ O with 0.1% TFA modifier) to afford compound 53. ¹ H-NMR (400MHz, DMSO-d ₆ ) δ12.44(s, 1H), 10.21(t, J=5.8Hz, 1H), 8.41(s, 1H), 7.22-7.15(m, 1H), 7.12 (dd,J=11.2,2.5Hz,1H),6.72(td,J=8.5,2.5Hz,1H),5.42(dd,J=9.6,4.1Hz,1H),5.07(s,1H),4.66( dd,J=12.8,4.1Hz,1H),4.58(s,1H),4.34(dd,J=5.6,2.4Hz,2H),4.04-3.91(m,2H),1.92(s,4H),1.82 (d,J=11.9Hz,1H),1.55(dt,J=12.4,3.5Hz,1H),0.80(q,J=6.3,5.7Hz,2H),0.72(q,J=6.0,4.9Hz, 2H). LCMS-ESI ⁺ (m/z): [ _M +H] ⁺ calcd for _C24H25FN3O6 : _{470.17 ;} found: 470.1.

Example 54

Preparation of compound 54

(2R,5S)-N-((S)-1-(2,4-difluorophenyl)-2,2,2-trifluoroethyl)-8-hydroxy-7,9-dioxo- 2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b] [1,3]oxaazepine-10-carboxamide

step 1

A 50-mL round bottom flask was charged with 54-A (0.02 g, 0.06 mmol), (S)-1-(2,4-difluorophenyl)-2,2, 2-trifluoroethylamine (0.019g, 0.09mmol), N,N-diisopropylethylamine (DIPEA) (0.048g, 0.38mmol) and HATU (0.036g, 0.09mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50 mL), washed with sat. NaHCO ₃ (2x), sat. NH ₄ Cl, and dried over Na ₂ SO ₄ . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to afford 54-B. LCMS _- ESI ⁺ (m/z ^{): [M+H]+} _{calcd for C18H19F2N2O7 :} 514; found: 514.

step 2

A 50-mL round bottom flask was charged with reactant 54-B (0.03 g, 0.058 mmol) and magnesium bromide (0.03 g, 0.15 mmol) in acetonitrile (2 mL). The reaction mixture was heated to 50 °C. After 10 minutes, the reaction mixture was cooled to 0 °C, and 1N hydrochloric acid (0.5 mL) was added. Then, the reaction mixture was diluted with MeOH (2 mL). after filtering. The crude material was purified by preparative HPLC (30-70% acetonitrile:water, 0.1% TFA) to give compound 54as TFA salt. ¹ H-NMR (400MHz, chloroform-d) δ11.28(d, J=9.4Hz, 1H), 8.39(s, 1H), 7.54(q, J=7.8Hz, 1H), 7.12-6.76(m, 2H),6.40-5.98(m,1H),5.57-5.18(m,2H),4.68(s,1H),4.29(dd,J=13.1,4.0Hz,1H),4.05(dd,J=12.9, 9.3Hz, 1H), 2.39-1.94(m, 4H), 1.86(t, J=10.5Hz, 1H), 1.60(dt, J=12.6, 3.4Hz, 1H). ¹⁹ F-NMR (376MHz, chloroform- d) δ-75.30 (t, J=6.8Hz, 3F), -108.33 (dd, J=8.6, 6.3Hz, 1F), -111.56--113.23 (m, 1F). LCMS-ESI ⁺ ( _m /z): [ _M +H] ⁺ _calcd for _C21H20F2N3O5 : ₅₀₀ .; found: 500.

Example 55

Preparation of compound 55

(1R,4S,12aS)-7-Hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12, 12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

step 1

A mixture of compound 55-A (40.60 g, 150 mmol) and Pd(OH) ₂ /C (12 g) in EtOH (400 mL) was stirred overnight at room temperature under H ₂ atmosphere. The reaction mixture was filtered and treated with HCl/EtOH (400 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to afford compound 55-B, which was used in the next step without purification. LCMS-ESI ⁺ (m/z): [M+H] ⁺ _Calc : _C9H16NO : 170.1.; Found: 170.2.

step 2

To a solution of compound 55-B (92.25 g, 0.45 mol) and K ₂ CO ₃ (186.30 g, 1.35 mol) in CH ₃ CN (1 L) was added benzyl bromide (76.50 g, 0.45 mol) at 0°C ). The mixture was stirred overnight at room temperature. The reaction mixture was filtered, concentrated and the residue was purified by silica gel chromatography to give compound 55-C.

step 3

To a mixture of diisopropylamine (50 g, 0.50 mol) in THF (400 mL) was added n-BuLi (200 mL, 0.50 mol) at -78 °C under _N2 atmosphere. After 0.5 h, the reaction mixture was warmed to 20 °C and stirred for 0.5 h. The mixture was cooled to -78 °C, and a solution of compound 55-C (64.75 g, 0.25 mol) in THF (600 mL) was added under _N2 atmosphere. The mixture was stirred for 4 hours and quenched with saturated _NH4Cl solution. The mixture was extracted with EtOAc, and the organic layer was washed with brine, dried _{over Na2SO4} , filtered and concentrated. The residue was purified by silica gel chromatography to afford compound 55-D.

step 4

A mixture of compound 55-D (129.50 g 0.50 mol) in 4N HCl (1.30 L) was refluxed for 4 hours. The mixture was concentrated. The residue was purified by HPLC to give compound 55-E.

step 5

A mixture of compound 55-E (47 g, 176 mmol) and Pd(OH) ₂ /C (9 g) in EtOH (400 mL) was stirred overnight at room temperature under H ₂ atmosphere. The reaction mixture was concentrated to afford compound 55-F which was used in the next step without purification. ¹ H-NMR (400MHz, CDCl ₃ ) δ4.22(s, 1H), 4.06(s, 1H), 2.98-2.95(d, J=11.2Hz, 1H), 1.96-1.93(d, J=11.2Hz ,1H),1.86-1.82(m,2H),1.76-1.74(d,J＝9.2Hz,2H),1.49(s,1H).LCMS-ESI ⁺ (m/z):C ₇ H ₁₂ NO ₂ Theoretical value of [M+H] ⁺ : 142.1.; found value: 142.1.

step 6

To a mixture of compound 55-F (29.20 g, 165 mmol) and 2N NaOH solution (330 mL, 0.66 mol) in dioxane (120 mL) was added Boc ₂ O (39.60 g, 181 mmol) at 0°C. The reaction mixture was stirred overnight at room temperature. The mixture was adjusted to pH = 5-6 with 3N HCl and extracted with DCM. The organic layer was dried _{over Na2SO4} , filtered and concentrated to afford 55-G. ¹ H-NMR (400MHz, CDCl ₃ )δ4.40(s,1H),4.26(s,1H),2.89(s,1H),1.76-1.74(s,1H),1.69-1.59(m,4H) , 1.50 (s, 1H), 1.47 (s, 9H). LCMS-ESI ⁺ (m/z): [M+Na] ⁺ Theoretical for C ₁₂ H ₁₉ NNaO ₄ : 264.1.; Found: 264.1.

step 7

To a mixture of compound 55-G (500 mg, 2.07 mmol) in THF (10 mL) chilled to 0 °C was slowly added BH ₃ -DMS THF complex (2N in THF, 8.23 mmol, 4.1 mL). Gas evolution occurs. Monitor internal temperature to ensure no significant exotherm. The reaction was allowed to warm to room temperature overnight. By LC/MS, some starting material remained, an additional 2 mL of BH3 _- DMS THF complex was added, and the mixture was stirred for another 3 h, then cooled to 0 °C and slowly quenched with methanol (gas evolution occurred) . The internal temperature was monitored to ensure that the exotherm was less than 25°C. The mixture was concentrated and purified by silica gel chromatography (20-40% EtOAc/hexanes) to afford 55-H.

Step 8

Compound 55 was prepared as described in Example 41, substituting 55-H for 41-B to afford compound 55. ¹ H-NMR (400MHz, DMSO-d6) δ11.81(s, 1H), 10.40(t, J=5.8Hz, 1H), 8.39(s, 1H), 7.19(t, J=8.6Hz, 2H) ,4.59-4.48(m,4H),4.16(t,J=12.2Hz,1H),4.03(d,J=12.2Hz,1H),2.69(s,1H),1.75(d,J=10.1Hz, 1H), 1.69-1.55 (m, 5H). ¹⁹ F NMR (376MHz, DMSO-d6) δ-109.3 (m, 1F), -112.5 (m, 1F). LCMS-ESI ⁺ (m/z): [M of C ₂₁ H ₁₉ F ₃ N ₃ O ₄ +H] ⁺ Theoretical value: 434.13.; Measured value: 434.32.

Example 56

Preparation of compound 56

(1R,2S,4R,12aR)-2-fluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4, 6,8,12,12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

step 1

A solution of 56-A (5 g, 19.43 mmol) in tetrahydrofuran (65 mL) was cooled in an ice bath while 0.5 M 9-borabicyclo[3.3.1]nonane (48.58 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature. After 18 hours, the reaction was cooled to 0 °C and a mixture of 2M sodium hydroxide (34 mL) and hydrogen peroxide (9.34 mL, 97.15 mmol) was added dropwise. After 2 hours at 0 °C, the reaction was allowed to warm to room temperature and stirred for 1 hour. The mixture was diluted with EtOAc and washed with water. The aqueous fraction was extracted with EtOAc, and the combined organic fractions were dried ( _{Na2SO4 )} and concentrated. The residue was purified by silica column chromatography (50-70% EtOAc/hexanes) to afford 56-B (3.05 g, 57%). LCMS-ESI ⁺ (m/z): [ _M +H] ⁺ calcd for C16H21NO3: _275.34 ; found: _276.122 .

step 2

To a solution of 56-B (1.45 g, 5.27 mmol) in N,N-dimethylformamide (12 mL) was added tert-butylchlorodiphenylsilane (1.51 mL, 5.79 mmol) and imidazole (1.08 g, 15.8 mmol). After 18 h, the mixture was diluted with water, extracted into EtOAc (2x), and the organic fractions were combined, dried ( _{Na2SO4 )} and concentrated. The residue was purified by silica column chromatography (10-20% EtOAc/hexanes) to afford 56-C (2.6 g, 96.1%). LCMS-ESI ⁺ (m/z): [ _M +H] ⁺ calcd for _C32H39NO3Si : 513.74; found: _514.625 .

step 3

To a solution of 56-C (3.27 g, 6.36 mmol) in EtOH (26 mL) and acetic acid (3 mL) was added 10% PdOH/C (0.52 g, 3.7 mmol) and the suspension was shaken at 50 atm in a Parr apparatus solution for 20 hours. After filtering through celite, the filter cake was washed with EtOH and the filtrate was concentrated under vacuum. The residue was dissolved in ethanol (26 mL) and acetic acid (3 mL, 52.4 mmol), treated with 10% PdOH/C (0.52 g, 3.7 mmol), and shaken at 50 atm in a Parr apparatus for 20 hours. Filtration through celite, washing the filter cake with EtOH, and concentrating the filtrate to dryness under vacuum gave the crude deprotected product (2.07 g, 79.4%). LCMS-ESI ⁺ (m/z): [ _M +H] ⁺ calcd for _C24H31NO3Si : _409.59 ; found: 410.485.

To the crude residue (2 g, 4.88 mmol) and di-tert-butyl dicarbonate 97% (2.14 g, 9.79 mmol) in THF (20 mL) was added N,N-diisopropylethylamine (DIPEA) (2.14 mL, 12.27mmol). After 20 h, the reaction mixture was diluted with water, extracted into EtOAc (2x), and the two organic fractions were washed with water, combined, dried ( _{Na2SO4 )} and concentrated. The residue was purified by silica column chromatography (10-20% EtOAc/hexanes) to afford 56-D (2.13 g, 86.14%). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calcd for _C30H41NO5Si : _523.74 ; found: _523.922 .

step 4

A solution of 56-D (2.07 g, 4.06 mmol) in THF (20 mL) was stirred in an ice bath while 2.0 M LiBH ₄ in THF (4.07 mL) was added, and the resulting mixture was stirred at room temperature for 18 h . Afterwards, the reaction mixture was diluted with ethyl acetate and treated slowly with water. The two phases were separated and the aqueous fraction was extracted again with ethyl acetate. The two organic fractions were washed with water, combined, dried ( _{Na2SO4 )} and concentrated. The residue was purified by silica column chromatography (20-40% EOAc/hexanes) to afford 56-E (1.59 g, 81.3%). LCMS-ESI ⁺ (m/z): C ₂₈ H ₃₉ NO ₄ Si [M+H] ⁺ Theoretical value: 481.7; found value: 482.337.

step 5

A mixture of 56-E (1.58 g, 3.28 mmol), phthalimide (0.79 g, 5.38 mmol) and triphenylphosphine (1.93 g, 7.37 mmol) in THF (90 mL) was cooled in an ice bath . Diisopropyl azodicarboxylate 95% (1.46 mL, 7.42 mmol) was added. Then, the mixture was allowed to warm to room temperature and stirred for 20 hours. Afterwards, the reaction mixture was concentrated, and the residue was dissolved in ether, cooled in an ice bath and stirred for 1.5 hours. The solid was filtered off, and the filtrate was concentrated. The residue was purified by silica column chromatography (10-30% EtOAc/hexanes) to afford the protected amino compound (1.86 g, 92.8%).

A solution of protected amino compound 56-F (1.85 g, 3.03 mmol) and hydrazine hydrate (0.6 mL, 12.39 mmol) in ethanol (19 mL) was stirred at 70 °C for 2 hours. The reaction mixture was cooled in an ice bath, diethyl ether (10 mL) was added, and the mixture was stirred for 30 minutes. The solid formed was filtered off, and the filtrate was concentrated to dryness under vacuum.

step 6

Crude amino compound 56-F (991 mg, 2.06 mmol), compound 38-F (Example 38) (714 mg, 2.06 mmol) and NaHCO ₃ (347 mg, 4.12 mmol) were dissolved in water (15 mL) and EtOH (15 mL). The mixture was stirred for 20 hours. The reaction mixture was concentrated under vacuum, and the residue was partitioned between water and EtOAc. The aqueous layer was re-extracted with EtOAc, the combined organic layers were dried ( _{Na2SO4 )} and concentrated. The residue (1.5 g) was dissolved in _CH2Cl2 ( ₅ mL), and 4N HCl in dioxane (18.6 mL) was added. After 1.5 hours, the mixture was concentrated to dryness, co-evaporated with toluene, and dried in vacuo.

The crude residue (1.38 g) and DBU (1.4 mL, 9.38 mmol) in toluene (25 mL) were stirred at 110 °C. After 35 minutes, the mixture was concentrated, and the residue was purified by silica column chromatography (5-15% MeOH/EtOAc) to afford 56-G (450 mg, 72.3%). LCMS-ESI ⁺ (m/z): [M+H] ⁺ _calcd for _C39H42N2O6Si : _{662.85 ;} found: 663.766.

step 7

A mixture of 56-G (890 mg, 1.34 mmol) in MeOH (14 mL) and THF (14 mL) was stirred at room temperature while 1M KOH (7.09 mL) was added. After 30 min, the reaction mixture was neutralized with 1N HCl, extracted into EtOAc (2x), the combined organic extracts were dried ( _{Na2SO4 )} and concentrated.

A suspension of the crude residue (850 mg), 2,4,6-trifluorobenzylamine (248 mg, 1.54 mmol) and HATU (662 mg, 1.74 mmol) in dichloromethane (5 mL) was stirred at room temperature, N,N-Diisopropylethylamine (DIPEA) (1.63 mL, 9.37 mmol) was added simultaneously. After 1 hour, additional 2,4,6-difluorobenzylamine (32 mg, 0.2 mmol), HATU (153 mg, 0.4 mmol) and N,N-diisopropylethylamine (DIPEA) (0.12 mL) were added ,0.67mmol). After 30 minutes, the mixture was diluted with water, extracted into EtOAc (3x), the combined organic phases were dried ( _{Na2SO4 )} , concentrated, and chromatographed on a silica column (50-75% EtOAc/Hexanes) The residue was purified to give 56-H (919 mg, 88.23%). LCMS _- ESI ⁺ (m/z): [ _M +H] ⁺ calcd for _{C44H42F3N3O5Si} : _777.9 ; found: _778.409 .

Step 8

A solution of 56-H (915 mg, 1.18 mmol) in THF (5 mL) was stirred in an ice bath. Simultaneously 1.0 M tetrabutylammonium fluoride in THF (1.18 mL) was added dropwise. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo, the residue was diluted with EtOAc, washed with water, dried ( _{Na2SO4 )} , concentrated, and chromatographed by silica column (50-75% EtOAc/hexanes, then 5% MeOH/EtOAc) The residue was purified. The resulting material (248mg, 0.46mmol) was dissolved in dichloromethane (2mL) cooled to -78°C, while diethylaminosulfurtrifluoride (0.07mL, 0.55mmol) was added dropwise, and the reaction was warmed up to room temperature and stirred for 1 hour. The reaction was cooled in an ice bath and quenched with saturated _NaHCO3 , the _two phases were separated, and the separated aqueous fraction was extracted with _CH2Cl2 . The two organic fractions were combined, dried ( _{Na2SO4 )} and concentrated. Purification of the residue by silica column chromatography (1% MeOH/EtOAc) gave 56-J (75 mg) (LCMS-ESI ⁺ (m/z): [M+H of C ₂₈ H ₂₃ F ₄ N ₃ O ₄ ] ⁺ Theoretical: 541.49; Found: 542.320) and 56-I (30 mg) (LCMS-ESI ⁺ (m/z): [M+H] ⁺ Theoretical: C ₂₈ H ₂₂ F ₃ N ₃ O ₄ : 521.49; found: 522.05).

step 9

Compound 56-J (75 mg, 139 mmol) was dissolved in TFA (1 mL), stirred at room temperature for 10 min, and the solution was concentrated. The residue was purified by reverse phase HPLC (Gemini, 15 to 43% ACN/ _H2O + 0.1% TFA) to afford compound 56. ¹ H-NMR (400MHz, DMSO-d6) δ10.67(s, 1H), 7.80(s, 1H), 7.17(t, J=8.6Hz, 2H), 5.45-5.18(m, 1H), 4.70- 4.39(m,3H),4.23(d,J=11.5Hz,1H),4.11-3.85(m,2H),2.85(dd,J=4.2,2.0Hz,1H),2.34-2.13(m,1H) ,1.81(s,1H),1.55-1.33(m,2H). ¹⁹ F-NMR (376 MHz, DMSO-d ₆ ) δ-74.20 (m), -106.95--116.45 (m), -190.65--194.54 (m).

Example 57

Preparation of compound 57

(1R,4R,12aR)-2,2-Difluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4 ,6,8,12,12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

step 1

A solution of 57-A (1.45 g, 5.34 mmol) in dichloromethane (30 mL) was cooled in an ice bath while adding Dess Martin (Dess Martin) periodinane (4.53 g, 10.69 mmol) in portions. The reaction was stirred at room temperature for 18 hours. _The reaction was quenched by adding water, the precipitate was filtered off, and saturated _{Na2S2O3 solution} was added. _The mixture was stirred until a biphasic solution turned, then saturated _NaHCO3 was added and the aqueous layer was extracted with _CH2Cl2 . The combined organic fractions were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by silica column chromatography (30-50% EtOAc/hexanes) to afford 57-B (1.13 g, 78.2%). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calcd for _C13H19NO5 : _269.29 ; found: _269.722 .

step 2

A solution of 57-B (0.5g, 1.86mmol) in dichloromethane (10mL) was cooled to -78°C, while diethylaminosulfur trifluoride (0.52mL, 3.91mmol) was added dropwise, and the reaction was allowed to warm to room temperature , and stirred for 18 hours. The reaction was cooled in an ice bath and quenched with saturated _NaHCO3 , the _two phases were separated, and the separated aqueous fraction was extracted with _CH2Cl2 . The two organic fractions were combined, dried ( _{Na2SO4 )} and concentrated. The residue was purified by silica column chromatography (20-50% EtOAc/hexanes) to afford 57-C (518 mg, 95.39%). ¹ H-NMR (400MHz, chloroform-d) δ4.43(s, 1H), 4.36-4.27(m, 1H), 4.22(s, 1H), 3.75(s, 3H), 2.95(t, J＝8.1 Hz, 1H), 2.30-1.98(m, 2H), 1.85-1.71(m, 1H), 1.44(m, 9H).

step 3

A solution of 57-C (935 mg, 3.21 mmol) in THF (10 mL) was stirred in an ice bath while 2.0 M LiBH ₄ in THF (3.22 mL) was added, and the resulting mixture was stirred at room temperature for 18 hours. After that, the reaction mixture was diluted with ethyl acetate, and water was slowly added. The two phases were separated and the separated aqueous fraction was extracted with ethyl acetate. The two organic fractions were washed with water, combined, dried ( _{Na2SO4 )} and concentrated. The residue was purified by silica column chromatography (20-40% EtOAc/hexanes) to afford 57-D (724 mg, 85.67%). ¹ H-NMR (400MHz, chloroform-d) δ4.30-3.48 (m, 5H), 2.75-2.56 (m, 1H), 2.24-1.90 (m, 3H), 1.86-1.65 (m, 1H), 1.47 (s,9H).

step 4

A mixture of 57-D (720 mg, 2.74 mmol), phthalimide (402 mg, 2.73 mmol) and triphenylphosphine (1.61 g, 6.15 mmol) in THF (45 mL) was cooled in an ice bath. Diisopropyl azodicarboxylate 95% (1.22 mL, 6.19 mmol) was added. Then, the mixture was allowed to warm to room temperature and stirred for 20 hours. Afterwards, the reaction mixture was concentrated, and the residue was dissolved in ether, cooled in an ice bath and stirred for 1.5 hours. After filtering off the solid, the filtrate was concentrated. The residue was purified by silica column chromatography (40-60% EtOAc/hexanes) to afford the phthalimide adduct (1.07 g, 99.7%). LCMS-ESI ⁺ (m/z): [ _{M +} H] ⁺ Calc: _C20H22F2N2O4 : _392.4 ; Found: _393.204 .

A solution of phthalimide adduct (1.07 g, 2.73 mmol) and hydrazine hydrate (0.54 mL, 11.15 mmol) in ethanol (10 mL) was stirred at 70 °C for 2 hours. The reaction mixture was cooled in an ice bath, and diethyl ether (10 mL) was added. The mixture was stirred for 30 minutes. The solid that formed was filtered off, and the filtrate was concentrated in vacuo to afford crude 57-E.

step 5

A mixture of crude 57-E (709 mg, 2.7 mmol), compound 38-F (Example 38) (936 mg, 2.7 mmol) and NaHCO ₃ (454 mg, 5.41 mmol)) in water (15 mL) and EtOH (15 mL) Stir for 20 hours. The reaction mixture was concentrated under vacuum, and the residue was partitioned between water and EtOAc. The aqueous layer was re-extracted with EtOAc, the combined organic layers were dried ( _{Na2SO4 )} and concentrated. The residue (1.5 g) was dissolved in _{CH2Cl2 (} 7 mL), and 4N HCl in dioxane (26.9 mL) was added. After 1.5 hours, the mixture was concentrated to dryness, co-evaporated with toluene, and dried in vacuo. The crude residue (1.3 g) and DBU (2 mL, 13.4 mmol) in toluene (25 mL) were stirred at 110 °C. After 35 minutes, the mixture was concentrated, and the residue was purified by silica column chromatography (5-15% MeOH/EtOAc) to afford 57-F (426 mg, 36.17%). LCMS _- ESI ⁺ (m/z): [M ₊ H] ⁺ _calcd for _C23H22F2N2O5 : 444.43; found: _445.280 .

step 6

A mixture of compound 57-F (426 mg, 0.96 mmol) in MeOH (7 mL) and THF (7 mL) was stirred at room temperature while 1M KOH (5.06 mL) was added. After 30 min, the reaction mixture was neutralized with 1N HCl, extracted into EtOAc (2x), the combined organic extracts were dried ( _{Na2SO4 )} and concentrated to crude 57-G.

step 7

A mixture of crude residue 57-G (189 mg), 2,4,6-trifluorobenzylamine (95 mg, 0.59 mmol) and HATU (276 mg, 0.73 mmol) in dichloromethane (3 mL) was stirred at room temperature The suspension was simultaneously added with N,N-diisopropylethylamine (DIPEA) (0.59 mL, 3.4 mmol). After 1 h, the mixture was diluted with water and extracted into EtOAc (3x). The combined organic phases were dried (Na ₂ SO ₄ ), and concentrated to 57-H. LCMS-ESI ⁺ (m/z): [ _{M +} H] ⁺ calcd for _C28H22F5N3O4 : _559.48 ; found: _560.24 .

Step 8

Compound 57-H (150 mg, 0.27 mmol) was dissolved in TFA (2 mL), stirred at room temperature for 10 min, and the solution was concentrated. The residue was purified by reverse phase HPLC (Gemini, 15 to 60% ACN/H ₂ O + 0.2% TFA) to give compound 57 (85 mg, 67.5%). LCMS-ESI ⁺ (m/z): [ _{M +} H] ⁺ Calc: _C21H16F5N3O4 : _469.36 ; Found: _470.229 . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ10.41(t, J=5.6Hz, 1H), 8.20(s, 1H), 7.12(t, J=8.7Hz, 2H), 4.79(s, 1H ),4.48(m,3H),4.10(m,2H),3.02(d,J=5.7Hz,1H),2.33(m,1H),2.22-1.97(m,2H),1.85(d,J= 11.0Hz, 1H), 1.21(s, 1H). ¹⁹ F NMR (376MHz, DMSO-d ₆ ) δ-69.88, -71.77, -74.09, -88.33 (dd, J＝222.6, 23.8Hz), -109.15- -109.60(m), -110.04, -112.44(t, J=7.6Hz).

Example 58

Preparation of Compound 58

(1R,4R,12aR)-N-(3-Chloro-2,4-difluorobenzyl)-2,2-difluoro-7-hydroxy-6,8-dioxo-1,2,3 ,4,6,8,12,12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

step 1

The crude residue 57-G (120 mg), 3-chloro,2,4-difluorobenzylamine (67 mg, 0.38 mmol) and HATU (175 mg, 0.46 mmol) were stirred in dichloromethane (3 mL) at room temperature , while adding N,N-diisopropylethylamine (DIPEA) (0.38 mL, 0.28 mmol). After 1 h, the mixture was diluted with water and extracted into EtOAc (3x). The combined organic phases were dried ( _{Na2SO4 )} and concentrated to afford 58-A. LCMS-ESI ⁺ (m/z ^{): [M+H]+} _{calcd for C28H22ClF4N3O4 : 575.94} ; found: 576.394.

step 2

Compound 58-A (166 mg) was dissolved in TFA (2 mL), stirred at room temperature for 10 min, and the solution was concentrated. The residue was purified by reverse phase HPLC (Gemini, 15 to 70% ACN/H ₂ O + 0.1% TFA) to give compound 57 (60 mg, 42.8%). LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value of C ₂₁ H ₁₆ ClF ₄ N ₃ O ₄ : 485.82; measured value: 486.135. ¹ H-NMR (400MHz, DMSO-d6) δ10. 77(t, J=6.0Hz, 1H), 7.77(s, 1H), 7.28(m, 2H), 4.77(s, 1H), 4.64-4.40(m, 2H), 4.27(d, J=9.1Hz ,1H),3.93(m,2H),2.95(d,J=5.8Hz,1H),2.51(s,1H),2.42-2.17(m,1H),2.14-1.89(m,2H),1.77( m, 1H). ¹⁹ F-NMR (376 MHz, DMSO-d ₆ ) δ-87.63, -88.23, -108.67, -109.27, -116.42 (t, J=7.0 Hz), -118.48 (d, J=7.8 Hz).

Example 59

Preparation of Compound 59

(1R,2R,4R,12aR)-2-fluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4, 6,8,12,12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

step 1

A solution of 57-B (1.9 g, 7.06 mmol) in methanol (35 mL) was stirred at 0 °C while sodium borohydride (667 mg, 17.64 mmol) was added portionwise, and the resulting mixture was stirred at room temperature for 30 min. The reaction mixture was cooled in an ice bath, quenched by adding water and concentrated. The residue was partitioned between water and EtOAc. The aqueous layer was re-extracted with EtOAc, the combined organic layers were dried ( _{Na2SO4 )} and concentrated. The residue was purified by silica column chromatography (30-60% EtOAc/hexanes) to afford 59-A (1.49 g). ¹ H-NMR (400MHz, chloroform-d) δ4.57(s, 1H), 4.52-4.42(m, 2H), 4.28(s, 1H), 4.14(s, 1H), 3.72(d, J=2.1 Hz,3H),2.74(s,1H),2.08-1.87(m,2H),1.43(d,J＝23.1Hz,10H)and 57-A(96mg): ¹ H-NMR(400MHz,chloroform-d )δ4.65-4.40(m,2H),4.34-4.02(m,1H),3.73(d,J＝2.3Hz,3H),2.74(t,J＝5.3Hz,1H),2.12-1.55(m ,3H), 1.52-1.18(m,11H).

step 2

To a solution of 59-A (686 mg, 2.53 mmol) in N,N-dimethylformamide (5 mL) was added tert-butylchlorodiphenylsilane (0.723 mL, 2.78 mmol) and imidazole (516 mg, 7.56 mmol) ). After 18 h, the mixture was diluted with water, extracted into EtOAc (2x), and the organic fractions were combined, dried ( _{Na2SO4 )} and concentrated. The residue was purified by silica column chromatography (10-20% EtOAc/hexanes) to give 59-C _. LCMS _- ESI ⁺ (m/z): [M+H] ⁺ theory for _C29H39NO5Si Value: 509.71; Found: 510.793.

step 3

In an ice bath, a solution of 59-C (1.23 g, 2.41 mmol) in THF (13 mL) was stirred while 2.0 M LiBH ₄ in THF (2.42 mL, 4.84 mmol) was added and the resulting The mixture was 18 hours. After diluting the reaction mixture with ethyl acetate, water was added slowly, the two phases were separated, and the separated aqueous fraction was extracted with ethyl acetate. The two organic fractions were washed with water, combined, dried ( _{Na2SO4 )} and concentrated. The residue was purified by silica column chromatography (20-40% EtOAC/hexanes) to afford 59-D. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calcd for _C28H39NO4Si : _481.7 ; found: _482.741 .

step 4

A mixture of 59-D (963 mg, 2.0 mmol), phthalimide (482 mg, 3.28 mmol) and triphenylphosphine (1.18 g, 4.49 mmol) in THF (50 mL) was cooled in an ice bath. Diisopropyl azodicarboxylate, 95% (0.89 mL, 4.52 mmol) was added. Then, the mixture was allowed to warm to room temperature and stirred for 20 hours. Afterwards, the reaction mixture was concentrated, and the residue was dissolved in ether, cooled in an ice bath and stirred for 1.5 hours. Afterwards, the solid was filtered off and the filtrate was concentrated. The residue was purified by silica column chromatography (10-30% EtOAc/hexanes) to afford the phthalimide adduct. LCMS-ESI ⁺ (m/z): [M+H] ⁺ _calcd for _C36H42N2O5Si : _610.81 ; found: _611.935 .

A solution of phthalimide adduct (1.2 g, 1.97 mmol) and hydrazine hydrate (0.4 mL, 8.03 mmol) in ethanol (12 mL) was stirred at 70 °C for 2 hours. The reaction mixture was cooled in an ice bath, and diethyl ether (10 mL) was added, and the mixture was stirred for 30 minutes. The solid that formed was filtered off, and the filtrate was concentrated to dryness in vacuo to afford 59-E. LCMS-ESI ⁺ (m/z): [M+H] ⁺ _calcd for _C28H40N2O3Si : _480.71 ; found: _481.356 .

step 5

A mixture of crude 59-E (770 mg, 1.60 mmol), compound 38-F (Example 38) (555 mg, 1.60 mmol) and NaHCO ₃ (269 mg, 3.20 mmol) in water (12 mL) and EtOH (12 mL) was stirred 20 hours. The reaction mixture was concentrated under vacuum, and the residue was partitioned between water and EtOAc. The aqueous layer was re-extracted with EtOAc, the combined organic layers were dried ( _{Na2SO4 )} , and concentrated.

The residue (1.29 g) was dissolved in _CH2Cl2 ( ₄ mL), and 4N HCl in dioxane (15.6 mL) was added. After 1.5 hours, the mixture was concentrated to dryness, co-evaporated with toluene, and dried in vacuo. LCMS-ESI ⁺ (m/z): [M+H] ⁺ _calcd for _C41H48N2O7Si : _708.91 ; found: _709.782 .

The crude residue (1.09 mg) and DBU (1.17 mL, 7.8 mmol) in toluene (20 mL) were stirred at 110 °C. After 35 minutes, the mixture was concentrated and the residue was purified by silica column chromatography (5-15% MeOH/EtOAc) to afford 59-F. LCMS-ESI ⁺ (m/z): [M+H] ⁺ _calcd for _C39H42N2O6Si : _{662.85 ;} found: 663.677.

step 6

A mixture of 59-F (680 mg, 1.03 mmol) in MeOH (10 mL) and THF (10 mL) was stirred at room temperature and 1M KOH (5.42 mL) was added. After 30 min, the reaction mixture was neutralized with 1N HCl, extracted into EtOAc (2x), the combined organic extracts were dried ( _{Na2SO4 )} and concentrated. LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value for C ₃₇ H ₃₈ N ₂ O ₆ Si: 634.79; found value: 635.466.

A suspension of the crude residue (650 mg), 2,4,6-trifluorobenzylamine (214 mg, 1.33 mmol) and HATU (623 mg, 1.64 mmol) in dichloromethane (6 mL) was stirred at room temperature, N,N-Diisopropylethylamine (DIPEA) (1.34 mL, 7.68 mmol) was added simultaneously. After 2 hours, the mixture was diluted with water, extracted into EtOAc (3x), the combined organic phases were dried ( _{Na2SO4 )} , concentrated and chromatographed on a silica column (50-75% EtOAc/Hexanes) The residue was purified to give 59-G. LCMS _- ESI ⁺ (m/z): [ _M +H] ⁺ Theoretical for _{C44H42F3N3O5Si} : _777.9 ; found: _778.566 .

step 7

A solution of 59-G (648 mg, 0.83 mmol) in THF (10 mL) was stirred in an ice bath while 1.0 M tetrabutylammonium fluoride in THF (0.83 mL) was added dropwise and the resulting mixture was stirred at room temperature 30 minutes. Additional 1.0 M tetrabutylammonium fluoride in THF (0.1 mL) was added dropwise. After 30 min, the reaction mixture was concentrated in vacuo and the residue was diluted with EtOAc, washed with water, dried ( _{Na2SO4 )} , concentrated, and the residue was purified by silica column chromatography (5% MeOH/EtOAc). A solution of the residue (290 mg, 0.54 mmol) in dichloromethane (3 mL) was cooled to -78 °C while diethylaminosulfur trifluoride (0.09 mL, 0.65 mmol) was added dropwise, the reaction was allowed to warm to room temperature and stirred 2.5 hours. The reaction was cooled in an ice bath, quenched with saturated _NaHCO3 , the _two phases were separated, and the separated aqueous fraction was extracted with _CH2Cl2 . The two organic fractions were combined, dried ( _{Na2SO4 )} and concentrated. The residue was purified by silica column chromatography (1% MeOH/EtOAc) to afford 59-H. LCMS-ESI ⁺ (m/z): [ _M ^+H]+ _calcd for _C28H23F4N3O4 : _541.49 ; found: 542.320.

Step 8

Compound 59-H (103 mg, 0.19 mmol) was dissolved in TFA (1.4 mL) at room temperature for 15 min, and the solution was concentrated. The residue was suspended in DMF, filtered off, and the precipitated product was washed with water and dried under vacuum to afford compound 59. LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value of C ₂₁ H ₁₇ F ₄ N ₃ O ₄ : 451.37, measured value: 452.226. ¹ H-NMR (400MHz, DMSO-d6) δ11. 53(s,1H),10.35(t,J=5.8Hz,1H),8.34(s,1H),7.18(t,J=8.6Hz,2H),5.15-4.88(m,1H),4.73(d ,J=3.3Hz,1H),4.49(m,3H),4.04(t,J=12.4Hz,1H),3.65(dd,J=12.4,3.7Hz,1H),2.95-2.76(m,1H) ,2.26-2.03(m,1H),1.96-1.64(m,3H). ¹⁹ F-NMR (376 MHz, DMSO-d ₆ ) δ-73.93, -74.74 (d, J=28.8 Hz), -109.31 (m), -112.51 (m), -165.65 (m).

Example 60

Preparation of compound 60

(1R,4S,12aR)-N-(2,3-Dichlorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a- Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

step 1

To a solution of dimethyl 3-methoxy-4-oxo-4H-pyran-2,5-dicarboxylate (5.5 g, 23 mmol) in MeOH (100 mL) was added 41-E (Example 41 ) (5g, 22mmol) and sodium bicarbonate (3.6g, 43mmol). The solution was stirred at room temperature for 1.5 hours. 4M HCl (in dioxane, 55 mL, 221 mmol) was added and the solution was heated to 50 °C for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The resulting oil was dissolved in sodium bicarbonate and washed with EtOAc. Then, the aqueous layer was extracted with _{CH2Cl2 (} 4x). _The combined _CH2Cl2 extracts _were dried over _Na2SO4 and concentrated to afford 60-A. LCMS _- ESI ⁺ (m/z): [M+H] ⁺ _calcd for _C16H19N2O5 : 319.13; found: _319.20 .

step 2

To a suspension of 60-A (3.7 g, 11.6 mmol) in MeOH (12 mL) and THF (23 mL) was added aqueous KOH (2M, 15.7 mL, 31.4 mmol). The resulting solution was stirred at room temperature for 10 minutes. The volatiles were removed in vacuo and the resulting aqueous layer was acidified with 1N HCl. The resulting white solid was filtered, washed with water, and dried in vacuo to afford 60-B. ¹ H-NMR (400MHz, chloroform-d) δ8.36(s, 1H), 5.01(d, J=2.7Hz, 1H), 4.12(s, 4H), 3.90(t, J=12.2Hz, 1H) , 3.78 (dd, J = 12.1, 3.1 Hz, 1H), 2.69 (s, 1H), 1.95-1.71 (m, 4H), 1.70-1.54 (m, 2H). LCMS _- ESI ⁺ (m/z): [M+H] ⁺ _calcd for _C15H17N2O5 : _305.11 ; found: 305.15.

step 3

To a solution of 60-B (0.10 g, 0.33 mmol) in CH ₂ Cl ₂ (3.5 mL) was added (2,3-dichlorophenyl)methanamine (0.12 g, 0.70 mmol), HATU (0.25 g, 0.66mmol) and N,N-diisopropylethylamine (DIPEA) (0.29mL, 1.64mmol). The resulting solution was stirred at room temperature until the reaction was judged complete by LC/MS. _The reaction mixture was diluted with _CH2Cl2 and washed with 1N HCl. The aqueous layer was back extracted with _CH2Cl2 , and the combined organic layers _were dried _{over Na2SO4} and dried in vacuo. The crude material was dissolved in hot DMF and allowed to precipitate on cooling. Filtration yielded 60-C. LCMS-ESI ⁺ (m/z): [ _{M +} H] ⁺ _calcd for _{C22H22Cl2N3O4} : _462.10 ; found: 462.14.

step 4

To a slurry of 60-C (0.11 g, 0.24 mmol) in acetonitrile (4.5 mL) was added magnesium bromide (0.089 g, 0.48 mmol). The reaction mixture was heated to 45°C for 2.5 hours and then cooled to room temperature. _The slurry was diluted with _CH2Cl2 and washed with 1N HCl and brine. The aqueous layer was back extracted with _CH2Cl2 ( _2x ), and the combined organic layers _were dried over _Na2SO4 and in vacuo. The crude solid was triturated with methanol and filtered to give 60. ¹ H-NMR(400MHz,DMSO-d6)δ11.72(s,1H),10.50(t,1H),8.34(s,1H),7.55(dd,1H),7.40-7.24(m,2H), 4.67(s,1H),4.61(d,2H),4.45(dd,1H),3.95(t,1H),3.84-3.73(m,1H),1.86-1.67(m,3H),1.66-1.40( m,4H).LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value of C ₂₁ H ₂₀ Cl ₂ N ₃ O ₄ : 448.08; found value: 448.18.

Example 61

Preparation of Compound 61

(1R,4S,12aS)-N-(3-Chloro-2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8, 12,12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Similar to Example 60, tert-butyl (1S,3S,4R)-3-(aminomethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (in Example 55 prepared) in place of 41-E, and (3-chloro-2,4-difluorophenyl)methanamine in place of (2,3-dichlorophenyl)methanamine, 61 was prepared. ¹ H-NMR (400MHz, DMSO-d6) δ11.85(s, 1H), 10.45(t, 1H), 8.40(s, 1H), 7.37(td, 1H), 7.27(td, 1H), 4.63- 4.46(m,4H),4.17(t,1H),4.04(dt,1H),1.76(d,1H),1.73-1.54(m,5H).LCMS-ESI ⁺ (m/z):C ₂₁ H [M+H] ⁺ Calc for ₁₉ ClF ₂ N ₃ O ₄ : 450.10; Found: 450.15.

Example 62

Preparation of Compound 62

'(2R,5S,13aR)-N-(4-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7 ,9,13,13a-Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine -10-Carboxamide

Compound 62 was prepared in a manner similar to compound 42, using (4-fluoro-2-(trifluoromethyl)phenyl)methanamine instead of (2,4,6-trifluorophenylphenyl)methanamine. ¹ H-NMR (400MHz, chloroform-d) δ10.50(s,1H),8.38(s,1H),7.57(dd,1H),7.36(dd,1H),7.19(td,1H),5.40- 5.28(m,2H),4.79(t,2H),4.69(s,1H),4.25(dd,1H),4.03(dd,1H),2.17-1.98(m,4H),1.96-1.84(m, 1H), 1.61 (dt, 1H). LCMS-ESI ⁺ ( _m /z): [ _{M +} H] ⁺ Theoretical for _C22H20F4N3O5 : 482.13; found: _482.145 .

Example 63

Preparation of compound 63

(2R,5S,13aR)-N-(2-Chloro-4-fluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a -Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Compound 63 was prepared in a manner similar to compound 42, using (2-chloro-4-fluorophenyl)methylamine instead of (2,4,6-trifluorophenylphenyl)methylamine. ¹ H-NMR (400MHz, chloroform-d) δ10.48(s,1H),8.45(s,1H),7.39(dd,1H),7.12(dd,1H),6.93(td,1H),5.37( d,1H),5.31(t,1H),4.68(s,3H),4.29(d,1H),4.04(t,1H),2.21-2.01(m,4H),1.97-1.82(m,1H) , 1.67-1.56 (m, 1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Theoretical for C ₂₁ H ₂₀ ClFN ₃ O ₅ : 448.10; Found: 448.143.

Example 64

Preparation of compound 64

(2R,5S,13aR)-8-Hydroxy-7,9-dioxo-N-(2,4,5-trifluorobenzyl)-2,3,4,5,7,9,13, 13a-Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Compound 64 was prepared in a manner similar to compound 42, using (2,4,5-trifluorophenyl)methylamine instead of (2,4,6-trifluorophenylphenyl)methylamine. ¹ H-NMR (400MHz, chloroform-d) δ10.42(s,1H),8.42(s,1H),7.19(ddd,1H),6.91(td,1H),5.38(dd,1H),5.31( t,1H),4.69(s,1H),4.61(d,2H),4.29(dd,1H),4.05(dd,1H),2.18-2.02(m,4H),1.96-1.84(m,1H) ,1.66-1.56(m,1H).LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value of C ₂₁ H ₁₉ F ₃ N ₃ O ₅ : 450.12; found value: 450.119.

Example 65

Preparation of compound 65

(2R,5S,13aR)-N-(5-Chloro-2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9, 13,13a-Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10- Formamide

Compound 65 was prepared in a manner similar to compound 42, using (5-chloro-2,4-difluorophenyl)methanamine instead of (2,4,6-trifluorophenylphenyl)methanamine. ¹ H-NMR (400MHz, chloroform-d) δ10.47(t, 1H), 8.41(s, 1H), 7.40(dd, 1H), 6.90(t, 1H), 5.37(dd, 1H), 5.31( t,1H),4.69(s,1H),4.62(d,2H),4.28(d,1H),4.04(dd,1H),2.17-2.02(m,4H),1.94-1.86(m,1H) , 1.61 (dt, 1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Theoretical for C ₂₁ H ₁₉ ClF ₂ N ₃ O ₅ : 466.09; Found: 466.107.

Example 66

Preparation of compound 66

(1R,4S,12aR)-N-(3,4-Difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a- Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 66 was prepared in a manner similar to compound 60, using (3,4-difluorophenyl)methylamine instead of (2,3-dichlorophenyl)methylamine. ¹ H-NMR (400MHz, chloroform-d) δ10.59(s,1H),7.24-7.16(m,2H),7.14-7.04(m,2H),4.91(s,1H),4.58(d,3H ),3.94-3.82(m,1H),3.79(d,1H),1.99-1.81(m,4H),1.76(d,1H),1.70-1.60(m,3H).LCMS-ESI ⁺ (m/ z): [M+H] ⁺ Theoretical for C ₂₁ H ₂₀ F ₂ N ₃ O ₄ : 416.13; Found: 416.415.

Example 67

Preparation of compound 67

(1R,4S,12aR)-N-(4-fluoro-2-(trifluoromethyl)benzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6, 8,12,12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 67 was prepared in a manner similar to compound 60, using (4-fluoro-2-(trifluoromethyl)phenyl)methanamine instead of (2,3-dichlorophenyl)methylamine. ¹ H-NMR (400MHz, chloroform-d) δ11.72(s, 1H), 10.55(s, 1H), 8.29(s, 1H), 7.61(s, 1H), 7.36(dd, 1H), 7.18( td,1H),4.91(s,1H),4.80(d,3H),4.11(s,1H),1.99-1.80(m,4H),1.76(d,1H),1.71-1.47(m,3H) .LCMS-ESI ⁺ (m/z): [M+H] ⁺ Calc for C ₂₂ H ₂₀ F ₄ N ₃ O ₄ : 466.13; Found: 466.297.

Example 68

Preparation of Compound 68

(1R,4S,12aR)-N-(2-Chloro-4-fluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a -Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 68 was prepared in a manner similar to compound 60, using (2-chloro-4-fluorophenyl)methylamine instead of (2,3-dichlorophenyl)methylamine. ¹ H-NMR (400MHz, chloroform-d) δ11.68(s,1H),10.52(s,1H),8.27(s,1H),7.44-7.37(m,1H),7.11(dd,1H), 6.93(td,1H),4.90(s,1H),4.68(d,2H),4.16-4.01(m,1H),3.88-3.70(m,2H),2.00-1.79(m,4H),1.75( d, 1H), 1.70-1.57 (m, 2H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Theoretical for C ₂₁ H ₂₀ ClFN ₃ O ₄ : 432.10; Found: 432.214.

Example 69

Preparation of compound 69

(1R,4S,12aR)-N-(3-Chloro-2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8, 12,12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 69 was prepared in a manner similar to compound 60, using (3-chloro-2,4-difluorophenyl)methanamine instead of (2,3-dichlorophenyl)methanamine. ¹ H-NMR (400MHz, chloroform-d) δ11.71(s, 1H), 10.48(s, 1H), 8.26(s, 1H), 7.27(s, 1H), 6.92(td, 1H), 4.90( s,1H),4.66(d,2H),4.08(s,1H),3.91-3.69(m,2H),2.01-1.79(m,3H),1.75(d,1H),1.71-1.44(m, 2H). LCMS-ESI ⁺ (m/z): [ _{M +} H] ⁺ _calcd for _{C21H19ClF2N3O4} : _450.10 ; found: 450.27.

Example 70

Preparation of compound 70

(1R,4S,12aR)-N-(2-fluoro-3-methylbenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12, 12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 70 was prepared in a manner similar to compound 60, using (2-fluoro-3-methylphenyl)methanamine instead of (2,3-dichlorophenyl)methanamine. ¹ H-NMR (400MHz, chloroform-d) δ11.62(s, 1H), 10.39(s, 1H), 8.30(s, 1H), 7.19(t, 1H), 7.07(t, 1H), 6.96( t,1H),4.89(d,1H),4.67(d,2H),4.08(s,1H),3.88-3.67(m,2H),2.26(d,3H),1.97-1.79(m,3H) , 1.78-1.39 (m,3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Theoretical for C ₂₂ H ₂₃ FN ₃ O ₄ : 412.16; Found: 412.26.

Example 71

Preparation of compound 71

(1R,4S,12aR)-N-(3,6-dichloro-2-fluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8, 12,12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 71 was prepared in a manner similar to compound 60, using (3,6-dichloro-2-fluorophenyl)methanamine instead of (2,3-dichlorophenyl)methanamine. ¹ H-NMR (400MHz, chloroform-d) δ11.62(s,1H),10.47(t,1H),8.29(s,1H),7.13(dd,1H),4.88(s,1H),4.85- 4.73(m,2H),4.09(d,1H),3.88-3.68(m,2H),1.99-1.53(m,8H).LCMS-ESI ⁺ (m/z):C ₂₁ H ₁₉ Cl ₂ FN ₃ [M+H] ⁺ theoretical value for O ₄ : 466.07; found value: 466.257.

Example 72

Preparation of compound 72

(1R,4S,12aR)-N-(3-Chlorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro- 1,4-Methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 72 was prepared in a manner similar to compound 60, using (3-chlorophenyl)methylamine instead of (2,3-dichlorophenyl)methylamine. ¹ H-NMR(400MHz,DMSO-d6)δ11.75(s,1H),10.44(t,1H),8.38(s,1H),7.42-7.22(m,4H),4.68(s,1H), 4.54(d,2H),4.48(dd,1H),3.97(t,1H),3.81(dd,1H),2.58(s,1H),1.87-1.69(m,3H),1.68-1.51(m, 2H), 1.46 (d, 1H). LCMS-ESI ⁺ (m/z): [ _M ^+H]+ _Theoretical for _C21H21ClN3O4 : _414.11 ; found: 414.21.

Example 73

Preparation of compound 73

(1R,4S,12aR)-N-(3-Chloro-2,6-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8, 12,12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 73 was prepared in a manner similar to compound 60, using (3-chloro-2,6-difluorophenyl)methanamine instead of (2,3-dichlorophenyl)methanamine. ¹ H-NMR (400MHz, DMSO-d6) δ11.71(s, 1H), 10.46(t, 1H), 8.34(s, 1H), 7.60(td, 1H), 7.19(td, 1H), 4.67( s,1H),4.62(d,2H),4.44(dd,1H),3.95(t,1H),3.78(dd,1H),2.57(s,1H),1.86-1.68(m,3H),1.67 -1.49(m,2H), 1.45(d,1H).LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value of C ₂₁ H ₁₉ ClF ₂ N ₃ O ₄ : 450.10; found value: 450.16.

Example 74

Preparation of compound 74

(1R,4S,12aR)-N-(2-fluoro-3-(trifluoromethyl)benzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6, 8,12,12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 74 was prepared in a manner similar to compound 60, using (2-fluoro-3-(trifluoromethyl)phenyl)methanamine instead of (2,3-dichlorophenyl)methylamine. ¹ H-NMR (400MHz, DMSO-d6) δ11.76(s, 1H), 10.48(t, 1H), 8.36(s, 1H), 7.68(q, 2H), 7.38(t, 1H), 4.68( s,1H),4.65(d,2H),4.47(dd,1H),3.96(t,1H),3.80(dd,1H),2.57(s,1H),1.88-1.69(m,3H),1.67 -1.50(m,2H),1.45(d,1H).LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value of C ₂₂ H ₂₀ F ₄ N ₃ O ₄ : 466.13; measured value: 466.142.

Example 75

Preparation of compound 75

(1R,4S,12aR)-N-(3-Chloro-4-fluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a -Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 75 was prepared in a manner similar to compound 60, using (3-chloro-4-fluorophenyl)methylamine instead of (2,3-dichlorophenyl)methylamine. ¹ H-NMR(400MHz,DMSO-d6)δ11.75(s,1H),10.43(t,1H),8.38(s,1H),7.51(dd,1H),7.42-7.28(m,2H), 4.68(s,1H),4.51(d,2H),4.47(dd,1H),3.97(t,1H),3.80(dd,1H),2.58(s,1H),1.86-1.68(m,3H) ,1.68-1.52(m,2H),1.46(d,1H).LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value of C ₂₁ H ₂₀ ClFN ₃ O ₄ : 432.10; measured value: 432.159.

Example 76

Preparation of compound 76

(1R,4S,12aR)-N-((3,5-difluoropyridin-2-yl)methyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6, 8,12,12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 76 was prepared in a manner similar to compound 60, using (3,5-difluoropyridin-2-yl)methanamine instead of (2,3-difluoropyridylphenyl)methanamine. ¹ H-NMR (400MHz, chloroform-d) δ10.80(s, 1H), 8.81(s, 1H), 8.33(d, 1H), 7.20(td, 1H), 4.90(s, 1H), 4.82( s,2H),4.28(d,1H),3.92-3.75(m,2H),3.48(s,2H),1.98-1.80(m,3H),1.77(d,1H),1.71-1.58(m, 2H). LCMS-ESI ⁺ (m/z ^{): [M+H]+} _{Theoretical for C20H19F2N4O4 : 417.13} ; Found: 417.189.

Example 77

Preparation of compound 77

(1R,4S,12aR)-7-Hydroxy-6,8-dioxo-N-((R)-1-(2,4,6-trifluorophenyl)ethyl)-1,2,3 ,4,6,8,12,12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

step 1

A 50-mL round bottom flask was charged with 77-A (0.15 g, 0.39 mmol), (R)-1-(2,4,6-trifluorophenyl)ethylamine ( 0.14g, 0.78mmol), N,N-diisopropylethylamine (DIPEA) (0.25g, 1.97mmol) and HATU (0.29g, 0.79mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50 mL), washed with sat. NaHCO ₃ (2x), sat. NH ₄ Cl, and dried over Na ₂ SO ₄ . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to afford 77-B as a white solid. LCMS-ESI ⁺ (m/z): [M+H] ⁺ , found: 538.

step 2

A 50-mL round bottom flask was charged with 77-B (0.20 g, 0.27 mmol) in TFA (2 mL). The reaction mixture was stirred for 30 minutes at room temperature. The solution was concentrated and the residue was purified by column chromatography on silica gel using EtOAc-20% MeOH in EtOAc as eluent to afford compound 77. ¹ H-NMR (400MHz, chloroform-d) δ10.67(d, J=8.2Hz, 1H), 8.22(s, 1H), 6.61(t, J=8.4Hz, 2H), 5.60(dd, J= 8.1,6.9Hz,1H),4.85(s,1H),3.82(t,J=12.2Hz,1H),3.71(dd,J=12.4,3.4Hz,1H),2.75-2.55(m,3H), 1.97-1.57(m,9H). ¹⁹ F-NMR (376MHz, chloroform-d) δ-109.65′--111.29(m), -111.76--113.09(m).LCMS-ESI ⁺ (m/z): [M+H] ⁺ measured value: 448.

Example 78

Preparation of compound 78

(2R,13aR)-8-Hydroxy-7,9-dioxo-N-((R)-1-(2,4,6-trifluorophenyl)ethyl)-2,3,4,5 ,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxa Aza-10-carboxamide

step 1

A 50-mL round bottom flask was charged with 78-A (0.30 g, 0.94 mmol), (R)-1-(2,4,6-trifluorophenyl)ethylamine ( 0.39 g, 1.87 mmol), N,N-diisopropylethylamine (DIPEA) (0.61 g, 4.87 mmol) and HATU (0.71 g, 1.87 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50 mL), washed with sat. NaHCO ₃ (2x), sat. NH ₄ Cl, and dried over Na ₂ SO ₄ . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to afford 78-B as a white solid. LCMS-ESI ⁺ (m/z): [M+H] ⁺ ; found: 478.

step 2

A 50-mL round bottom flask was charged with 78-B (0.4 g, 0.84 mmol) and magnesium bromide (0.4 g, 2.2 mmol) in acetonitrile (5 mL). The reaction mixture was heated to 50 °C. After 10 minutes, the reaction mixture was cooled to 0 °C, and 1N hydrochloric acid (4 mL) was added. More water (-5 mL) was added and the solid was filtered, washed with water and dried to afford compound 78. ¹ H-NMR (400MHz, chloroform-d) δ12.30(s, 1H), 10.59(d, J=8.3Hz, 1H), 8.21(s, 1H), 6.60(t, J=8.4Hz, 2H) ,5.59(t,J=7.4Hz,1H),5.37(dd,J=9.4,4.1Hz,1H),5.31-5.09(m,1H),4.64(t,J=3.0Hz,1H),4.20( dd, J = 12.9, 4.1 Hz, 2H), 3.96 (dd, J = 12.8, 9.4 Hz, 2H), 2.21-1.85 (m, 4H), 1.71-1.43 (m, 3H). ¹⁹ F-NMR (376 MHz, chloroform-d) δ -110.37 (tt, J=8.7, 6.1 Hz), -112.19 (t, J=7.2 Hz). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 464.

Example 79

Preparation of compound 79

(1R,4S,12aR)-7-Hydroxy-6,8-dioxo-N-(2,4,5-trifluorobenzyl)-1,2,3,4,6,8,12, 12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

step 1

A 50-mL round bottom flask was charged with 79-A (0.12 g, 0.32 mmol), (2,4,5-trifluorophenyl)methanamine (0.10 g, 0.63 mmol) in DCM (10 mL) , N,N-Diisopropylethylamine (DIPEA) (0.20 g, 1.58 mmol) and HATU (0.24 g, 0.63 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50 mL), washed with sat. NaHCO ₃ (2x), sat. NH ₄ Cl, and dried over Na ₂ SO ₄ . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to afford 79-B as a white solid. LCMS-ESI ⁺ (m/z): [M+H] ⁺ ; found: 524.

step 2

A 50-mL round bottom flask was charged with 79-B (0.15 g, 0.29 mmol) in TFA (2 mL). The reaction mixture was stirred for 30 minutes at room temperature. The solution was concentrated and the residue was purified by column chromatography on silica gel using EtOAc-20% MeOH in EtOAc as eluent to afford compound 79. ¹ H-NMR (400MHz, chloroform-d) δ11.70(s, 1H), 10.65-10.18(m, 1H), 8.27(s, 1H), 7.26(m, 1H), 6.90(td, J=9.7 ,6.4Hz,1H),4.89(s,1H),4.60(d,J=6.0Hz,2H),4.09(dd,J=11.4,2.6Hz,1H),3.96-3.66(m,2H),2.68 (s,1H),2.15-1.43(m,6H). ¹⁹ F-NMR (376MHz, chloroform-d) ^{δ120.53--120.85} (m), -134.68--136.79(m), -142.26--144.11(m). M+H] ⁺ Found: 434.

Example 80

Preparation of Compound 80

(1R,4S,12aR)-N-(5-Chloro-2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8, 12,12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

step 1

A 50-mL round bottom flask was charged with 80-A (0.12 g, 0.32 mmol), (5-chloro-2,4-difluorophenyl)methanamine (0.11 g, 0.63 mmol), N,N-diisopropylethylamine (DIPEA) (0.20 g, 1.58 mmol) and HATU (0.24 g, 0.63 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in EtOAc (50 mL), washed with sat. NaHCO ₃ (2x), sat. NH ₄ Cl, and dried over Na ₂ SO ₄ . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to afford 80-B as a white solid. LCMS-ESI ⁺ (m/z): [M+H] ⁺ ; Found: 541.

step 2

A 50-mL round bottom flask was charged with 80-B (0.14 g, 0.26 mmol) in TFA (2 mL). The reaction mixture was stirred for 30 minutes at room temperature. The solution was concentrated and the residue was purified by column chromatography on silica gel using EtOAc-20% MeOH in EtOAc as eluent to afford compound 80. ¹ H-NMR (400MHz, chloroform-d) δ10.46(s, 1H), 8.27(s, 1H), 7.40(t, J=7.8Hz, 1H), 6.89(t, J=9.1Hz, 1H) ,4.90(s,1H),4.78-4.48(m,2H),4.08(dd,J=11.3,2.5Hz,1H),3.95-3.63(m,2H),2.68(s,1H),2.22-1.51 (m,7H). ¹⁹ F-NMR (376 MHz, chloroform-d) δ -113.37 (q, J=8.1 Hz), -116.37 (q, J=8.0 Hz). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 451.

Example 81

Preparation of compound 81

(1R,3S,4S,12aS)-3-fluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4, 6,8,12,12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

step 1

A 100-mL round bottom flask was charged with 81-A (1.0 g, 3.7 mmol) in DCM (10 mL). The reaction mixture was cooled to 0 °C. Diethylaminosulfur trifluoride (DAST) (0.58 mL, 4.1 mmol) was added slowly. Then, the reaction mixture was stirred at room temperature for 1 hour. The mixture was cooled back to 0 °C. The reaction was quenched by dropwise addition of saturated NaHCO ₃ (5 mL). Then, the reaction mixture was diluted with EtOAc (100 mL), washed with saturated NaHCO ₃ , brine, and dried over Na ₂ SO ₄ . After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 81-B. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 274.

step 2

A 100-mL round bottom flask was charged with 81-B (0.8 g, 3.0 mmol) in THF (10 mL). The reaction mixture was stirred at -78°C. 2.0M _LiBH4 in THF (3.2 mL, 6.4 mmol) was added slowly. Then, the reaction mixture was allowed to warm and stirred at room temperature for 3 hours. The reaction mixture was then diluted with EtOAc (100 mL) and treated slowly with water ( _H2 evolution). After separation of the two phases, the aqueous fraction was extracted with EtOAc, and the two organic fractions were combined, washed with water, and dried _{over Na2SO4} . After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 81-C. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 246.

step 3

A 100-mL round bottom flask was charged with 81-C (0.57 g, 2.3 mmol), triphenylphosphine (1.3 g, 5.1 mmol) and phthalimide (0.55 g, 3.7 mmol). Then, the reaction mixture was cooled to 0 °C while stirring. Diisopropyl azodicarboxylate (DIAD) (1.0 mL, 5.1 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred overnight at room temperature. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 81-D. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 375.

step 4

To a solution of 81-D (0.8 g, 2.1 mmol) in EtOH (40 mL) was added hydrazine monohydrate (0.6 mL). The reaction mixture was heated to 70°C while stirring for 3 hours. After the solids were removed by filtration, the filtrate was concentrated to afford 81-E. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 245.

step 5

A 100-mL round bottom flask was charged with 81-E (0.49 g, 2.0 mmol) and 81-F (0.7 g, 2.0 mmol) in ethanol (7 mL). Sodium bicarbonate (0.34 g, 4.0 mmol) in water (7 mL) was added to the reaction mixture. Then, the reaction mixture was stirred overnight at room temperature. The mixture was diluted with EtOAc (50 mL) and washed with water (2x). The aqueous fraction was extracted with EtOAc (1x), the organic fractions were combined, dried ( _{Na2SO4 )} and concentrated. Crude material 81-G was used in the next step without further purification. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 573.

step 6

A 100-mL round bottom flask was charged with 81-G (1.1 g, 1.9 mmol) in 4N HCl/dioxane (11 mL). Then, the reaction mixture was stirred at room temperature for 1 hour. After concentration, 1.0 g of the intermediate was obtained. This intermediate and DBU (1.3 g, 8.8 mmol) were dissolved in toluene (10 mL). The reaction mixture was heated to 110°C while stirring for 1 hour. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 81-H. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 413.

step 7

A 100-mL round bottom flask was charged with 81-H (0.56 g, 1.4 mmol) in THF (5 mL) and MeOH (5 mL). 1N KOH (4 mL) was added to the reaction mixture. Then, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified by adding 1N HCl (4 mL). After concentration, the residue was coevaporated with toluene (3x). Half of the crude acid, 2,4,6-trifluorobenzylamine (0.2 g, 1.3 mmol), N,N-diisopropylethylamine (DIPEA) (0.41 g, 3.1 mmol) and HATU (0.48 g, 1.25 mmol) was dissolved in DMF (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc (100 mL), washed with sat. NaHCO ₃ (2x), sat. NH ₄ Cl (2x), and dried over Na ₂ SO ₄ . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to afford 81-I. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 542.

Step 8

A 50 mL round bottom flask was charged with reactant 81-I (0.31 g, 0.58 mmol) in TFA (3 mL). The reaction mixture was stirred for 30 minutes at room temperature. After concentration, the crude material was purified by column chromatography on silica gel with EtOAc-MeOH to afford compound 81. ¹ H-NMR (400MHz, chloroform-d) δ10.29(s, 1H), 8.31(s, 1H), 6.65(dd, J=8.7, 7.5Hz, 2H), 5.05-4.75(m, 2H), 4.65(d, J=5.6Hz, 2H), 4.11(d, J=12.2Hz, 1H), 3.83(t, J=12.3Hz, 1H), 3.56(dd, J=12.3, 3.3Hz, 1H), 2.77 (s, 1H), 2.25-1.97 (m, 2H), 1.95 (d, J=11.0Hz, 2H), 1.77 (d, J=11.2Hz, 1H). ¹⁹ F-NMR (376MHz, chloroform-d) δ-108.98(t, J=8.2Hz), -112.03(t, J=7.2Hz), -168.00.LCMS-ESI ⁺ (m/z): measured value: 452.

Example 82

Preparation of Compound 82

(1S,3R,4R,12aR)-3-fluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4, 6,8,12,12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

step 1

A 100-mL round bottom flask was charged with 82-A (0.6 g, 2.1 mmol) in DCM (6 mL). The reaction mixture was cooled to 0 °C. DAST (0.35 mL, 3.0 mmol) was added slowly. Then, the reaction mixture was stirred at room temperature for 1 hour. The mixture was cooled back to 0 °C. The reaction was quenched by dropwise addition of saturated NaHCO ₃ (5 mL). Then, the reaction mixture was diluted with EtOAc (100 mL), washed with saturated NaHCO ₃ , brine, and dried over Na ₂ SO ₄ . After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 82-B. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 274.

step 2

A 100-mL round bottom flask was charged with 82-B (0.4 g, 1.5 mmol) in THF (10 mL). The reaction mixture was stirred at -78°C. 2.0M _LiBH4 in THF (1.6 mL, 3.2 mmol) was added slowly. Then, the reaction mixture was allowed to warm and stirred at room temperature for 3 hours. Then, the reaction mixture was diluted with EtOAc (100 mL), and water was added slowly ( _H2 evolution). After separation of the two phases, the aqueous fraction was extracted with EtOAc, and the two organic fractions were combined, washed with water, and dried _{over Na2SO4} . After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 82-C. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 246.

step 3

A 100-mL round bottom flask was charged with 82-C (0.25 g, 1.0 mmol), triphenylphosphine (0.59 g, 2.2 mmol) and phthalimide (0.24 g, 1.6 mmol). Then, the reaction mixture was cooled to 0 °C while stirring. DIAD (0.44 mL, 2.2 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred overnight at room temperature. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 82-D. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 375.

step 4

To a solution of 82-D (0.35 g, 0.9 mmol) in EtOH (20 mL) was added hydrazine monohydrate (0.3 mL). The reaction mixture was heated to 70°C while stirring for 3 hours. After the solids were removed by filtration, the filtrate was concentrated to afford 82-E. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 245.

step 5

A 100-mL round bottom flask was charged with 82-E (0.21 g, 0.87 mmol) and 82-F (0.3 g, 0.87 mmol) in ethanol (7 mL). Sodium bicarbonate (0.15 g, 1.7 mmol) in water (7 mL) was added to the reaction mixture. Then, the reaction mixture was stirred overnight at room temperature. The mixture was diluted with EtOAc (50 mL) and washed with water (2x). The aqueous fraction was extracted with EtOAc, the organic fractions were combined, dried ( _{Na2SO4 )} and concentrated. Crude material 82-G was used in the next step without further purification. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 573.

step 6

A 100-mL round bottom flask was charged with 82-G (0.49 g, 0.86 mmol) in 4N HCl/dioxane (5 mL). Then, the reaction mixture was stirred at room temperature for 1 hour. After concentration, 0.4 g of the intermediate were obtained. This intermediate and DBU (0.6 g, 4.0 mmol) were dissolved in toluene (10 mL). The reaction mixture was heated to 110°C while stirring for 1 hour. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 82-H. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 413.

step 7

A 100-mL round bottom flask was charged with 82-H (0.2 g, 0.49 mmol) in THF (5 mL) and MeOH (5 mL). Then, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified by adding 1N HCl (1.5 mL). After concentration, the residue was coevaporated with toluene (3x). Half of the crude acid, 2,4,6-trifluorobenzylamine (0.15 g, 0.95 mmol), N,N-diisopropylethylamine (DIPEA) (0.31 g, 2.4 mmol) and HATU (0.36 g, 0.95 mmol) was dissolved in D CM (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc (100 mL), washed with sat. NaHCO ₃ (2x), sat. NH ₄ Cl (2x), and dried over Na ₂ SO ₄ . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to afford 82-I. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 542.

Step 8

A 50 mL round bottom flask was charged with reactant 82-I (0.22 g, 0.41 mmol) in TFA (3 mL). The reaction mixture was stirred for 30 minutes at room temperature. After concentration, the crude material was purified by column chromatography on silica gel with EtOAc-MeOH to afford compound 82. ¹ H-NMR (400MHz, chloroform-d) δ10.25(s,1H),8.28(s,1H),6.65(s,2H),5.15-4.77(m,2H),4.65(s,2H), 4.32-3.41 (m, 2H), 2.78 (s, 1H), 1.86 (dd, J=144.8, 72.3Hz, 6H). ¹⁹ F-NMR (376MHz, chloroform-d) δ-108.98(t, J=8.2Hz), -112.03(t, J=7.2Hz), -168.00.LCMS-ESI ⁺ (m/z): measured value: 452.

Example 83

Preparation of compound 83

(1S,4R,12aS)-3,3-Difluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4 ,6,8,12,12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

step 1

A 100-mL round bottom flask was charged with 83-A (1.0 g, 3.7 mmol) in DCM (20 mL). The reaction mixture was cooled to 0 °C. Dess-Martin periodinane (1.8 g, 4.2 mmol) was added slowly. Then, the reaction mixture was stirred at room temperature for 3 hours. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 83-B. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 270.

step 2

A 100-mL round bottom flask was charged with 83-B (0.85 g, 3.2 mmol) in DCM (15 mL). The reaction mixture was cooled to 0 °C. DAST (1.5 mL, 11.3 mmol) was added slowly. Then, the reaction mixture was stirred overnight at room temperature. The mixture was cooled back to 0 °C. The reaction was quenched by dropwise addition of saturated NaHCO ₃ (5 mL). Then, the reaction mixture was diluted with EtOAc (100 mL), washed with saturated NaHCO ₃ , brine, and dried over Na ₂ SO ₄ . After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 83-C. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 292.

step 3

A 100-mL round bottom flask was charged with 83-C (0.44 g, 1.5 mmol) in THF (6 mL). The reaction mixture was stirred at -78°C. 2.0M _LiBH4 in THF (1.6 mL, 3.2 mmol) was added slowly. Then, the reaction mixture was allowed to warm and stirred at room temperature for 3 hours. Then, the reaction mixture was diluted with EtOAc (100 mL), and water was added slowly ( _H2 evolution). After separation of the two phases, the aqueous fraction was extracted with EtOAc, and the two organic fractions were combined, washed with water, and dried _{over Na2SO4} . After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 83-D. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 264.

step 4

A 100-mL round bottom flask was charged with 83-D (0.17 g, 0.65 mmol), triphenylphosphine (0.37 g, 1.4 mmol) and phthalimide (0.15 mmol) in THF (10 mL). g, 1.0 mmol). Then, the reaction mixture was cooled to 0 °C while stirring. DIAD (0.28 mL, 1.4 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred overnight at room temperature. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 83-E. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 393.

step 5

To a solution of 83-E (0.25 g, 0.64 mmol) in EtOH (20 mL) was added hydrazine monohydrate (0.3 mL). The reaction mixture was heated to 70°C while stirring for 3 hours. After the solids were removed by filtration, the filtrate was concentrated to afford 83-F. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 263.

step 6

A 100-mL round bottom flask was charged with 83-F (0.18 g, 0.69 mmol) and 83-G (0.324 g, 0.69 mmol) in ethanol (7 mL). Sodium bicarbonate (0.12 g, 1.4 mmol) in water (7 mL) was added to the reaction mixture. Then, the reaction mixture was stirred overnight at room temperature. The mixture was diluted with EtOAc (50 mL) and washed with water. The aqueous fraction was extracted with EtOAc, the organic fractions were combined, dried ( _{Na2SO4 )} and concentrated. Crude material 83-H was used in the next step without further purification. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 591.

step 7

A 100-mL round bottom flask was charged with 83-H (0.4 g, 0.68 mmol) in 4N HCl/dioxane (3.8 mL). Then, the reaction mixture was stirred at room temperature for 1 hour. After concentration, 0.35 g of the intermediate was obtained. This intermediate and DBU (0.51 g, 3.3 mmol) were dissolved in toluene (10 mL). The reaction mixture was heated to 110°C while stirring for 1 hour. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 83-I. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 431.

Step 8

A 100-mL round bottom flask was charged with 83-I (0.2 g, 0.47 mmol) in THF (5 mL) and MeOH (5 mL). 1N KOH (1.4 mL) was added to the reaction mixture. Then, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified by adding 1N HCl (1.4 mL). After concentration, the residue was coevaporated with toluene (3x). Half of the crude acid, 2,4,6-trifluorobenzylamine (0.14 g, 0.91 mmol), N,N-diisopropylethylamine (DIPEA) (0.29 g, 2.2 mmol) and HATU (0.35 g, 0.91 mmol) was dissolved in DCM (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc (100 mL), washed with sat. NaHCO ₃ (2x), sat. NH ₄ Cl (2x), and dried over Na ₂ SO ₄ . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to afford 83-J. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 560.

step 9

A 50 mL round bottom flask was charged with reactant 83-J (0.18 g, 0.32 mmol) in TFA (3 mL). The reaction mixture was stirred for 30 minutes at room temperature. After concentration, the crude material was purified by column chromatography on silica gel with EtOAc-MeOH to afford compound 83 as a white solid. ¹ H-NMR (400MHz, chloroform-d) δ10.29(d, J=6.1Hz, 1H), 8.34(s, 1H), 6.65(dd, J=8.7, 7.5Hz, 2H), 4.83(s, 1H), 4.72-4.58(m, 2H), 4.36-4.10(m, 2H), 4.05(t, J＝11.5Hz, 1H), 2.97(d, J＝4.4Hz, 1H), 2.49-2.08(m ,3H), 2.12-1.94(m,2H). ¹⁹ F-NMR (376MHz, chloroform-d) δ-92.32 (ddd, J = 225.6, 22.5, 9.1 Hz), -107.64--109.54 (m), -112.05 (t, J = 7.0 Hz), -114.67 ( d, J = 226.7 Hz). LCMS-ESI ⁺ (m/z): Found: 470.

Example 84

Preparation of Compound 84

(1S,2R,4S,12aR)-7-Hydroxy-2-methyl-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4 ,6,8,12,12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

step 1

A 100-mL round bottom flask was charged with 84-A (1.6 g, 5.9 mmol) in DCM (20 mL). The reaction mixture was cooled to 0 °C. Dess-Martin periodinane (4.9 g, 11.7 mmol) was added slowly. Then, the reaction mixture was stirred at room temperature for 3 hours. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 84-B. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 270.

step 2

A 100-mL round bottom flask was charged with 84-B (1.3 g, 4.8 mmol) in THF (30 mL). The reaction mixture was cooled to 0 °C. Tebbe's reagent (0.5M in toluene, 19.4 mL, 9.7 mmol) was added slowly. Then, the reaction mixture was stirred at room temperature for 2 hours. The mixture was cooled back to 0 °C. The reaction was quenched by dropwise addition of saturated NaHCO ₃ (5 mL). The reaction mixture was stirred for an additional 15 minutes at room temperature and filtered through celite. The filter cake was washed with DCM (2x). The combined filtrates were concentrated in vacuo and the residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 84-C. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 268.

step 3

To a solution of 84-C (0.9 g, 3.4 mmol) in EtOH (20 mL) purged with _N2 was added Pd/C (0.18 g). The mixture was stirred under _H2 for 3 h. The mixture was filtered through celite, and the filtrate was concentrated to afford 84-D. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 270.

step 4

A 100-mL round bottom flask was charged with 84-D (0.9 g, 3.3 mmol) in THF (6 mL). The reaction mixture was stirred at -78°C. 2.0M _LiBH4 in THF (13.2 mL, 26.4 mmol) was added slowly. Then, the reaction mixture was allowed to warm and stirred at room temperature for 3 hours. Then, the reaction mixture was diluted with EtOAc (100 mL), and water was added slowly ( _H2 evolution). After separation of the two phases, the aqueous fraction was extracted with EtOAc, and the two organic fractions were combined, washed with water, and dried _{over Na2SO4} . After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 84-E. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 242.

step 5

A 100-mL round bottom flask was charged with 84-E (0.4 g, 1.66 mmol), triphenylphosphine (0.96 g, 3.6 mmol) and phthalimide (0.39 mmol) in THF (15 mL). g, 2.7 mmol). Then, the reaction mixture was cooled to 0 °C while stirring. DIAD (0.7 mL, 3.6 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred overnight at room temperature. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 84-F. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 371.

step 6

To a solution of 84-F (0.55 g, 1.5 mmol) in EtOH (20 mL) was added hydrazine monohydrate (0.3 mL). The reaction mixture was heated to 70°C while stirring for 3 hours. After the solids were removed by filtration, the filtrate was concentrated to afford 84-G. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 241.

step 7

A 100-mL round bottom flask was charged with 84-G (0.35 g, 1.4 mmol) and 84-H (0.5 g, 1.4 mmol) in ethanol (10 mL). Sodium bicarbonate (0.24 g, 2.8 mmol) in water (10 mL) was slowly added to the reaction mixture. Then, the reaction mixture was stirred overnight at room temperature. The mixture was diluted with EtOAc (50 mL) and washed with water (2x). The aqueous fraction was extracted with EtOAc, the organic fractions were combined, dried ( _{Na2SO4 )} and concentrated. Crude material 84-I was used in the next step without further purification. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 583.

Step 8

A 100-mL round bottom flask was charged with 84-I (0.84 g, 1.4 mmol) in 4N HCl/dioxane (8.2 mL). Then, the reaction mixture was stirred at room temperature for 1 hour. After concentration, 0.74 g of the intermediate was obtained. This intermediate and DBU (1.1 g, 7.2 mmol) were dissolved in toluene (10 mL). The reaction mixture was heated to 110°C while stirring for 1 hour. After concentration, the residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 84-J. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 409.

step 9

A 100-mL round bottom flask was charged with 84-J (0.4 g, 0.98 mmol) in THF (5 mL) and MeOH (5 mL). 1N KOH (3.0 mL) was added to the reaction mixture. Then, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified by adding 1N HCl (3.0 mL). After concentration, the residue was co-evaporated with toluene (3x). Half of the crude acid, 2,4,6-trifluorobenzylamine (0.32 g, 1.96 mmol), N,N-diisopropylethylamine

(DIPEA) (0.63 g, 4.9 mmol) and HATU (0.74 g, 1.96 mmol) were dissolved in DCM (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc (100 mL), washed with sat. NaHCO ₃ (2x), sat. NH ₄ Cl (2x), and dried over Na ₂ SO ₄ . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to afford 84-K. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 538.

Step 10

A 50-mL round bottom flask was charged with 84-K (0.5 g, 0.93 mmol) in TFA (6 mL). The reaction mixture was stirred for 30 minutes at room temperature. After concentration, the crude material was purified by column chromatography on silica gel with EtOAc-MeOH to afford compound 84. ¹ H-NMR (400MHz, chloroform-d) δ10.37(s, 1H), 8.28(s, 1H), 6.65(t, J=8.1Hz, 2H), 4.80(s, 1H), 4.77-4.52( m,3H),4.08(d,J=13.1Hz,1H),3.88(d,J=12.3Hz,1H),2.47(d,J=3.2Hz,1H),2.35(s,1H),2.16( ddd, J=14.3, 11.2, 3.6Hz, 1H), 1.93-1.57(m, 3H), 1.29-1.19(m, 1H), 1.17(d, J=7.0Hz, 3H). ¹⁹ F-NMR (376 MHz, chloroform-d) δ -109.24, -111.98. LCMS-ESI ⁺ (m/z): Found: 448.

Example 85

Preparation of Compound 85

(6aS,7R,11S)-1-Hydroxy-2,13-dioxo-N-(2,4,6-trifluorobenzyl)-6,6a,7,8,9,10,11, 13-Octahydro-2H-7,11-methanopyrido[1',2':4,5]pyrazino[1,2-a]aza-3-carboxamide

step 1

A solution of 85-A (1100 mg, 3.855 mmol) in DMSO (6 mL) and water (0.75 mL) was stirred at room temperature while N-iodosuccinimide (885 mg, 3.934 mmol) was added. After 2 hours, additional N-iodosuccinimide (88 mg, 0.391 mmol) was added and the resulting mixture was stirred at room temperature for 1.5 hours. The dark brown reaction mixture was diluted with EtOAc and washed with a mixture of 10% aq.Na ₂ S ₂ O ₃ solution and aq.NaHCO ₃ solution (˜1:4 mixture), then water (with some brine). After extracting the aqueous fraction with EtOAc, the organic fractions were combined, dried ( _{Na2SO4 )} and concentrated. The residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 85-B. ¹ H-NMR (400MHz, CDCl ₃ ) δ7.51-7.44 (m, 2H), 7.33-7.17 (m, 3H), 4.22-4.05 (m, 2H), 4.02-3.86 (m, 2H), 3.77 ( d,J=5.3Hz,1H),3.54-3.44(m,1H),3.27(t,J=4.5Hz,1H),2.75-2.66(m,1H),2.30(dddd,J=14.8,13.1, 7.2,5.8Hz,1H),2.14(dddd,J＝14.8,13.0,6.1,2.1Hz,1H),1.97(d,J＝8.9Hz,1H),1.58-1.46(m,1H),1.45-1.34 (m, 4H), 1.24 (t, J=7.1Hz, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value of C ₁₈ H ₂₅ INO ₃ : 430.1; found value: 430.0 ..

step 2

A solution of 85-B (993 mg, 2.313 mmol), AIBN (305 mg, 1.857 mmol) and tributyltin hydride (1392 mg, 4.799 mmol) in toluene (15 mL) was stirred at 100 °C. After 2 hours, the reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with water and brine. After extracting the aqueous fraction with EtOAc, the organic fractions were combined, dried ( _{Na2SO4 )} and concentrated. The residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 85-C. ¹ H-NMR (400MHz, CDCl ₃ ) δ7.57-7.49 (m, 2H), 7.32-7.23 (m, 2H), 7.23-7.15 (m, 1H), 4.24-4.02 (m, 2H), 3.97 ( q, J=6.7Hz, 1H), 3.83(d, J=5.1Hz, 1H), 3.48(t, J=4.6Hz, 1H), 3.19-3.04(m, 1H), 2.58(p, J=4.0 Hz, 1H), 2.30(dddd, J=14.7, 13.1, 7.0, 4.5Hz, 1H), 1.98(d, J=11.2Hz, 1H), 1.64(tdd, J=13.3, 6.2, 2.6Hz, 1H) ,1.49-1.33(m,3H),1.37(d,J=6.7Hz,3H),1.32-1.26(m,1H),1.23(t,J=7.2Hz,3H).LCMS-ESI ⁺ (m/ z): [M+H] ⁺ calcd for C ₁₈ H ₂₆ NO ₃ : 304.2; found: 304.1.

step 3

85-C (725 mg, 2.39 mmol) and 20% Pd(OH) ₂ /C (351 mg) in EtOH (25 mL) were stirred with 4N HCl in dioxane (0.9 mL) under H ₂ atmosphere. mixture. After 2 hours, the reaction mixture was filtered, and the filtrate was concentrated. LCMS-ESI ⁺ (m/z): [ _M +H] ⁺ Calc: _C10H18NO3 : _200.13 ; Found: 200.1. After co-evaporating the residue with toluene (x2), the residue in THF (15 mL) and Boc ₂ O (720 mg, 3.299 mmol) were stirred at room temperature while adding N,N-diisopropylethylamine ( DIPEA) (1.2 mL, 6.889 mmol). After 1 hour, the reaction mixture was diluted with water and extracted with EtOAc (x2). After washing the organic extracts with water, the combined extracts were dried ( _{Na2SO4 )} and concentrated. The residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 85-D as a mixture of rotamers. ¹ H-NMR (400MHz, CDCl ₃ ) δ4.42-3.97 (m, 5H), 2.62 (d, J=5.6Hz, 1H), 2.45-2.26 (m, 1H), 2.25-2.15 (m, 1H) ,1.80(td,J=13.7,6.7Hz,1H),1.66(dd,J=12.3,6.6Hz,2H),1.55-1.70(m,2H),1.47(s,2H),1.42(s,7H ), 1.28 (dt, J = 9.5, 7.1 Hz, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical for C ₁₅ H ₂₆ NO ₅ : 300.2; found: 299.7.

step 4

To a solution of 85-D (568 mg, 1.897 mmol) and pyridine (0.25 mL, 3.091 mmol) in THF (5 mL) at 0 °C was added phenyl chlorothioformate (0.3 mL, 2.169 mmol), which was very Quickly produces insoluble material. After ~30 minutes at 0 °C, additional pyridine (0.3 mL, 3.709 mmol) and phenyl chlorothioformate (0.3 mL, 2.169 mmol) were added. After 1.5 h at 0 °C and 1 h at room temperature, the mixture was concentrated and the residue was dissolved in EtOAc and water. After separation of the two layers, the organic fraction was washed with ~0.1N HCl, saturated aqueous NaHCO ₃ and brine. After extracting the aqueous fraction with EtOAc, the combined organic fractions were dried ( _{Na2SO4 )} and concentrated. The residue was purified by flash chromatography using EtOAc/hexanes as eluent to afford 85-E. ¹ H-NMR (400MHz, CDCl ₃ ) δ7.47-7.37(m, 2H), 7.30(t, J=6.9Hz, 1H), 7.11(dd, J=8.0, 4.0Hz, 2H), 5.54(dt ,J=9.0,4.9Hz,1H),4.50(dt,J=9.8,5.3Hz,1H),4.35(dd,J=21.4,5.0Hz,1H),4.30-4.14(m,2H),2.71( s,1H),2.54(s,1H),2.14-2.00(m,1H),1.82(m,3H),1.54(m,1H),1.48(s,4.5H),1.45(s,4.5H) , 1.30 (dt, J = 9.4, 7.1 Hz, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calcd for _C22H30NO6S : _436.2 ; found: _435.8 .

step 5

A mixture of 85-E (602 mg, 1.382 mmol), AIBN (182 mg, 1.108 mmol) and tributyltin hydride (608 mg, 2.096 mmol) in toluene (8 mL) was stirred at 100 °C. After 1 h, the reaction mixture was concentrated, and the residue was dissolved in EtOAc, then washed with water and brine. After extracting the aqueous fraction with EtOAc, the combined organic fractions were dried ( _{Na2SO4 )} and concentrated. The residue was purified by flash chromatography using EtOAc/hexanes as eluent to afford 85-F as a mixture of rotamers. ¹ H-NMR (400MHz, CDCl ₃ ) δ4.37-4.06(m, 4H), 2.69-2.53(m, 1H), 2.11(m, 1H), 1.97(m, 0.65H), 1.93-1.80(m ,1.35H),1.54(s,5H),1.46(s,3.15H),1.42(s,5.85H),1.27(m,3H).LCMS-ESI ⁺ (m/z):C ₁₁ H ₁₈ NO [MC ₄ H ₈ +H] ⁺ theoretical value for ₄ : 228.1; found value: 227.9.

step 6

85-F (420 mg) was repurified, and the purified 85-F in THF (1.5 mL) was stirred at 0 °C while adding 2.0 M _LiBH4 in THF (1.5 mL). After 5 minutes, the mixture was stirred at room temperature for 17 hours, and additional 2.0M _LiBH4 in THF (1.5 mL) was added at room temperature. After 23 hours at room temperature, additional 2.0M _LiBH4 in THF (3 mL) was added and the resulting mixture was stirred for -72 hours. The reaction mixture was stirred at 0 °C while water was slowly added and further diluted with water, the product was extracted with EtOAc (x2). The extracts were washed with water, combined, dried ( _{Na2SO4 )} and concentrated. The residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 85-G. ¹ H-NMR (400MHz, CDCl ₃ ) δ4.12(t, J=5.3Hz, 1H), 3.99(dd, J=12.0, 7.9Hz, 1H), 3.85(dd, J=8.0, 4.7Hz, 1H ),3.73(dd,J=11.9,1.4Hz,1H),2.28(d,J=4.6Hz,1H),1.90-1.73(m,2H),1.68-1.45(m,6H),1.47(s, 9H), 1.43-1.33 (m, 1H). LCMS-ESI ⁺ (m/z): [MC ₄ H ₈ +H] ⁺ theoretical for C ₉ H ₁₆ NO ₃ : 186.1; found: 186.0.

step 7

In a 0°C bath, a solution of 85-G (198 mg, 0.820 mmol), phthalimide (200 mg, 1.359 mmol) and PPh ₃ (488 mg, 1.861 mmol) in THF (10 mL) was stirred while adding DIAD (0.36 mL, 1.828 mmol). After 30 minutes at 0°C, the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated and the residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 85-H as a mixture of rotamers. ¹ H-NMR (400MHz, CDCl ₃ ) δ7.82(dd, J=5.4, 3.1Hz, 2H), 7.69(dd, J=5.4, 3.1Hz, 2H), 4.46(s, 1H), 4.19(m ,2H),3.95(s,1H),2.31-2.14(m,1H),2.05(d,J=16.5Hz,1H),1.84(m,2H),1.79-1.70(m,1H),1.66( m,1H), 1.61-1.30(m,12H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Theoretical value: C ₂₁ H ₂₇ N ₂ O ₄ : 371.2; Measured value: 370.8.

Step 8

To a solution of 85-H (270 mg, 0.729 mmol) in EtOH (12 mL) was added hydrazine hydrate (0.145 mL, 3.083 mmol) at room temperature, and the resulting solution was stirred at 70 °C. After 1.5 hours, the mixture was cooled to 0°C and diluted with diethyl ether (30 mL) before stirring at 0°C for 1 hour. The mixture was filtered, and the filtrate was concentrated. _The residue was dissolved in _CH2Cl2 and filtered to remove some insoluble material. The obtained filtrate was concentrated. The residue mixed with 85-I (257 mg, 0.742 mmol) and NaHCO ₃ (131 mg, 1.559 mmol) in water (3 mL) and EtOH (3 mL) was stirred at room temperature. After 1 hour, the mixture was diluted with water and extracted with EtOAc (x2). After washing the extracts with water, the organic extracts were combined, dried ( _{Na2SO4 )} and concentrated. To a solution of the residue in _CH2Cl2 ( ₂ mL) was added 4N HCl in dioxane (6 mL). After 1.5 hours at room temperature, the solution was concentrated and co-evaporated with toluene. A mixture of the residue and DBU (0.6 mL, 4.012 mmol) in toluene (5 mL) was stirred in a 100 °C bath. After 1 hour, additional DBU (0.3 mL, 2.006 mmol) was added and the mixture was stirred at 100 °C for another 1 hour. After concentrating the mixture, the residue was purified by flash chromatography using EtOAc-20% MeOH/EtOAc as eluent to afford 85-J. ¹ H-NMR (400MHz, CDCl ₃ )δ8.08(s,1H),7.71-7.62(m,2H),7.36-7.29(m,2H),7.29-7.23(m,1H),5.44(d, J＝9.8Hz, 1H), 5.10(d, J＝9.8Hz, 1H), 4.44-4.28(m, 3H), 4.23(t, J＝13.0Hz, 1H), 3.99(ddt, J＝10.2, 6.3 ,3.6Hz,2H),2.44-2.36(m,1H),2.29(dt,J＝11.6,5.3Hz,1H),1.84(dt,J＝10.8,5.3Hz,2H),1.77-1.61(m, 3H), 1.57(d, J=11.7Hz, 1H), 1.48(ddd, J=20.9, 12.3, 5.5Hz, 1H), 1.38(t, J=7.1Hz, 3H).LCMS-ESI ⁺ (m/ z): [M+H] ⁺ calcd for C ₂₄ H ₂₇ N ₂ O ₅ : 423.2; found: 423.3.

step 9

A mixture of 85-J (214 mg, 0.507 mmol) in THF (4 mL) and MeOH (4 mL) was stirred at room temperature while 1 N KOH (1.1 mL) was added. After 30 minutes, the reaction mixture was concentrated to ~1 mL, acidified with 1 N HCl (~1.2 mL), and diluted with brine before extraction with _CH2Cl2 (20 mL x ₂ ). The combined extracts were dried ( _{Na2SO4 )} and concentrated to give the crude acid. LCMS _- ESI ⁺ (m/z): [M+H] ⁺ _calcd for _C22H23N2O5 : _395.2 ; found: 395.3.

A mixture of crude acid (199 mg, 0.505 mmol), 2,4,6-trifluorobenzylamine (130 mg, 0.807 mmol) and HATU (304 mg, 0.800 mmol) in CH ₂ Cl ₂ (6 mL) was stirred at room temperature. The mixture was simultaneously added with N,N-diisopropylethylamine (DIPEA) (0.62 mL, 3.559 mmol). After 30 min, the reaction mixture was concentrated, and the residue was dissolved in EtOAc, washed with saturated aqueous _NH4Cl (x2), saturated aqueous _NaHCO3 (x2) and brine. After extracting the aqueous fraction with EtOAc, the two organic fractions were combined, dried ( _{Na2SO4 )} and concentrated. The residue was purified by flash chromatography using EtOAc-20% MeOH/EA as eluent to afford 85-K. ¹ H-NMR (400MHz, CDCl ₃ ) δ10.40(t, J=5.7Hz, 1H), 8.42(s, 1H), 7.68-7.54(m, 2H), 7.33(ddd, J=7.7, 6.3, 1.5Hz, 2H), 7.30-7.26(m, 1H), 6.74-6.60(m, 2H), 5.37(d, J=10.0Hz, 1H), 5.17(d, J=10.0Hz, 1H), 4.76- 4.57(m, 2H), 4.46(dd, J=6.0, 4.3Hz, 1H), 4.34(t, J=12.4Hz, 1H), 4.07(dd, J=12.4, 3.6Hz, 1H), 3.91(dt ,J=12.4,3.9Hz,1H),2.52-2.44(m,1H),2.32(dd,J=11.8,6.2Hz,1H),1.92(dt,J=10.7,5.4Hz,1H),1.83- 1.70 (m, 3H), 1.67 (d, J=11.7Hz, 1H), 1.52 (dddt, J=25.5, 17.0, 11.8, 5.3Hz, 2H). ¹⁹ F-NMR (376MHz, CDCl ₃ ) δ-109.15(dq, J=15.0,7.5,7.1Hz,1F),-111.85(t,J=6.8Hz,2F).LCMS-ESI ⁺ (m/z) : [M+H] ⁺ Theoretical for C ₂₉ H ₂₇ F ₃ N ₃ O ₄ : 538.2; Found: 538.3.

Step 10

85-K (187 mg, 0.348 mmol) was dissolved in trifluoroacetic acid (3 mL) at room temperature and stirred at room temperature. After ₁ h, the solution was concentrated, and the residue was dissolved in _CH2Cl2 . After washing the solution with 0.1N HCl, the aqueous fraction was extracted with _CH2Cl2 ( _x2 ). The organic fractions were combined, dried ( _{Na2SO4 )} and concentrated. _The residue was purified by flash chromatography using _CH2Cl2-20 % MeOH in _CH2Cl2 as eluent to afford 150 _mg (96%) of compound 85. Compound 85 was further purified by recrystallization from methanol (10 mL) to afford compound 85. ¹ H-NMR (400MHz, CDCl ₃ ) δ12.09(s, 1H), 10.39(t, J=5.7Hz, 1H), 8.36(s, 1H), 6.74-6.48(m, 2H), 4.64(d , J=5.7Hz, 2H), 4.59(dd, J=6.1, 4.4Hz, 1H), 4.36-4.18(m, 2H), 4.12(dt, J=12.4, 4.1Hz, 1H), 2.68-2.47( m, 1H), 2.25-2.10(m, 1H), 2.10-1.98(m, 1H), 1.98-1.66(m, 4H), 1.66-1.48(m, 2H). ¹⁹ F-NMR (376MHz, CDCl ₃ )δ-109.23(ddd, J=15.1,8.6,6.0Hz,1F),-112.02(t,J=6.9Hz,2F).LCMS-ESI ⁺ (m/z):C ₂₂ H ₂₁ F ₃ N ₃ [M+H] ⁺ Theoretical for O ₄ : 448.2; Found: 448.3.

Example 86

Preparation of compound 86

(1R,3S,4R,12aS)-7-Hydroxy-3-methyl-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4 ,6,8,12,12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

step 1

A solution of 86-A (10.160 g, 39.48 mmol) in DMSO (52 mL) and water (6.5 mL) was stirred at room temperature while N-iodosuccinimide (8.888 g, 39.50 mmol) was added. After 30 minutes, the dark brown reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO ₃ , 10% aqueous Na ₂ S ₂ O ₃ and brine. After extracting the aqueous fraction with EtOAc, the organic fractions were combined, dried ( _{Na2SO4 )} and concentrated. The residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 86-B as a white solid. ¹ H-NMR (400MHz, CDCl ₃ ) δ7.33-7.19(m, 5H), 4.25-4.12(m, 1H), 3.79(q, J=1.6Hz, 1H), 3.72(q, J=6.5Hz ,1H),3.51(s,1H),3.47(s,3H),3.31(dd,J=3.9,1.6Hz,1H),2.76-2.69(m,1H),2.13(ddd,J=14.3,7.8 ,1.7Hz,1H),2.08-1.97(m,1H),1.91(dtd,J＝14.1,4.0,1.5Hz,1H),1.42(d,J＝6.5Hz,3H).LCMS-ESI ⁺ (m /z): [M+H] ⁺ for C ₁₆ H ₂₁ INO ₃ calc: 402.1; found: 402.0.

step 2

At 100°C, stir 86-B (12.468g, 31.07mmol), azobisisobutyronitrile (AIBN) (4.082g, 24.86mmol) and tributyltin hydride (18.047g, 62.22mmol) in toluene (150mL ) in the solution. After 30 minutes, the reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with water and brine. The aqueous fraction was extracted with EtOAc, the organic fractions were combined, dried ( _{Na2SO4 )} and concentrated. The residue was purified twice by flash chromatography using hexane-EtOAc as eluent to afford 86-C. ¹ H-NMR (400MHz, CDCl ₃ )δ7.39-7.31(m,2H),7.31-7.24(m,2H),7.24-7.17(m,1H),4.11(s,1H),3.72(s, 1H), 3.49(s, 3H), 3.33(d, J=3.4Hz, 1H), 3.27(d, J=6.4Hz, 1H), 2.65-2.51(m, 1H), 1.92(ddd, J=13.6 ,6.8,2.4Hz,1H),1.69-1.50(m,2H),1.47(d,J＝10.1Hz,1H),1.41(d,J＝6.6Hz,3H),1.21-1.07(m,1H) . LCMS-ESI ⁺ (m/z): [ _M +H] ⁺ calcd for _C16H22NO3 : 276.2; found: _276.1 .

step 3

Under _H2 atmosphere, stir 86-C (4.187 g, 15.21 mmol) and 20% Pd(OH) ₂ /C (1.022 g) in EtOH (100 mL) and 4N in dioxane (5.7 mL) Mixture of HCl. After 1.5 hours, the reaction mixture was filtered, and the filtrate was concentrated. After co-evaporating the residue with toluene, the residue was used in the next step. LCMS-ESI ⁺ (m/z): [ _M +H] ⁺ calcd for _C8H14NO3 : _172.1 ; found: 172.1.

After co-evaporating the residue with toluene, the residue and Boc ₂ O (5.712 g, 26.17 mmol) in THF (45 mL) were stirred at room temperature while N,N-diisopropylethylamine (DIPEA) was added (8 mL, 45.93 mmol). After 30 min, the reaction mixture was diluted with water and extracted with EtOAc (x2). After washing the organic extracts with water, the combined extracts were dried ( _{Na2SO4 )} and concentrated. The residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 86-D. ¹ H NMR spectrum showed a mixture of rotamers. ¹ H-NMR (400MHz, CDCl ₃ ) δ4.20(d, J=7.6Hz, 1H), 4.19-4.10(m, 2H), 4.08(d, J=3.5Hz, 1H), 3.72(s, 3H ), 2.74(d, J=5.6Hz, 1H), 1.97(ddd, J=13.6, 6.9, 2.8Hz, 1H), 1.88-1.78(m, 1H), 1.79-1.50(m, 1H), 1.46( s, 3H), 1.38 (s, 6H), 1.31 (d, J=13.3Hz, 1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value of C ₁₃ H ₂₂ NO ₅ : 272.2; found: 271.6.

step 4

In a bath at 0 °C, a solution of 86-D (1659 mg, 6.115 mmol) in _{CH2Cl2 (} 35 mL) was stirred while adding Dess-Martin periodinane (5.183 g, 12.22 mmol) in portions. After 5 minutes, the mixture was stirred at room temperature. After 2 hours, the reaction mixture was cooled in an ice bath, quenched with water, and filtered. The filtrate was washed with saturated NaHCO ₃ , dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 86-E. ¹ H NMR chromatogram showed two rotamers. ¹ H-NMR (400MHz, CDCl ₃ ) δ4.43(d, J=3.8Hz, 0.5H), 4.39(s, 1H), 4.26(s, 0.5H), 3.75(s, 3H), 3.10(s ,1H),2.24(d,J=4.5Hz,0.5H),2.19(d,J=4.4Hz,0.5H),2.12(d,J=4.4Hz,0.5H),2.07(d,J=4.2 Hz,0.5H),2.01(dd,J＝4.5,2.2Hz,0.5H),1.98(dt,J＝4.3,1.9Hz,0.5H),1.80(s,0.5H),1.77(s,0.5H ), 1.46(s, 4.5H), 1.40(d, J=2.8Hz, 4.5H). LCMS-ESI ⁺ (m/z): [MC ₄ H ₈ +H] ⁺ theory of C ₉ H ₁₂ NO ₅ Value: 214.1; Found: 213.8.

step 5

A solution of 86-E (528 mg, 1.961 mmol) in THF (12 mL) was stirred at 0 °C while a 0.5 M solution of Tebbe's reagent in toluene (7.9 mL, 3.95 mmol) was added dropwise. After the addition, the brown solution was slowly warmed to room temperature and stirred at room temperature for 2.5 hours. In a bath at 0 °C, the reaction mixture was stirred while quenching the reaction by the careful addition of saturated aqueous _NaHCO3 . After the mixture was diluted with _CH2Cl2 and stirred at room temperature for ₁₅ min, the resulting mixture was filtered through a pad of celite and the filter _cake was washed with _CH2Cl2 . After separation of the two fractions in the filtrate, the aqueous fraction was extracted with _CH2Cl2 and the organic fractions _were combined, dried ( _{Na2SO4 )} and concentrated. The residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 86-F. ¹ H NMR spectrum showed two rotamers. ¹ H-NMR (400MHz, CDCl ₃ )δ5.13(s,0.6H),5.04(s,0.4H),4.82-4.71(m,1H),4.55(s,0.6H),4.43(s,0.4 H),4.29(d,J=3.7Hz,0.4H),4.24(d,J=3.7Hz,0.6H),3.71(s,3H),2.84(s,1H),2.14(m,2H), 1.75(s,0.6H),1.74-1.70(s,0.4H),1.55(m,1H),1.45(s,3.6H),1.37(s,5.4H).LCMS-ESI ⁺ (m/z) : [M+H] ⁺ Calc for C ₁₄ H ₂₂ NO ₄ : 268.2; Found: 267.6.

step 6

A mixture of 86-F (333 mg, 1.246 mmol) and 20% Pd(OH) ₂ /C (53 mg) in EtOH (5 mL) was stirred under H ₂ atmosphere. After 30 minutes, the mixture was filtered, and the filtrate was concentrated to afford 86-G. ¹ H NMR spectrum showed two rotamers. ¹ H-NMR (400MHz, CDCl ₃ )δ4.20(m,1H),4.08(m,1H),3.71(two s,3H),2.68(m,1H),2.06(m,1H),1.80- 1.63(m,2H),1.63-1.51(m,1H),1.44(s,4H),1.38(s,5H),1.13(m,3H),0.92(m,1H).LCMS-ESI ⁺ (m /z): [M+H] ⁺ calcd for C ₁₄ H ₂₄ NO ₄ : 270.2; found: 269.7.

step 7

A solution of 86-G (336 mg, 1.482 mmol) in THF (5 mL) was stirred at 0° C. while 2.0 M LiBH ₄ in THF (1.5 mL) was added. After 5 minutes, the mixture was stirred at room temperature. After 2 hours, additional 2.0M _LiBH4 in THF (1.5 mL) was added. After 21 h, additional 2.0M _LiBH4 in THF (3 mL) was added. After 3 hours at room temperature, the solution was heated at 35°C for 18 hours. The reaction mixture was cooled to 0 °C and carefully quenched with water. After extracting the mixture with EtOAc (x2), the two organic fractions were washed with water, combined, dried ( _{Na2SO4 )} and concentrated. The residue was purified by flash chromatography using hexane-EtOAc to afford 86-H. ¹ H-NMR (400MHz, CDCl ₃ ) δ4.95-4.09 (br, 1H), 4.05 (s, 1H), 3.82 (dd, J=11.5, 7.7Hz, 1H), 3.76-3.69 (m, 1H) ,3.66(d,J=11.5Hz,1H),2.45(d,J=4.1Hz,1H),2.03(dqdd,J=11.4,7.0,4.5,2.6Hz,1H),1.77-1.57(m,2H ),1.48(dd,J=10.1,1.8Hz,1H),1.45(s,9H),1.00(d,J=6.9Hz,3H),0.93(ddd,J=13.2,4.7,2.6Hz,1H) .LCMS _- ESI ⁺ (m/z): [ _M +H] ⁺ calcd for _C13H24NO3 : 242.2; found: 241.7.

Step 8

In a bath at 0 °C, a solution of 86-H (218 mg, 0.903 mmol), phthalimide (218 mg, 1.482 mmol) and PPh ₃ (535 mg, 2.040 mmol) in THF (10 mL) was stirred while DIAD (0.40 mL, 2.032 mmol) was added. After 10 minutes at 0°C, the mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated and the residue was purified by flash chromatography using hexane-EtOAc as eluent to afford 86-I. ¹ H NMR showed two rotamers. ¹ H-NMR (400MHz, CDCl ₃ ) δ7.82 (dt, J=7.3, 3.6Hz, 2H), 7.70 (d, J=5.3Hz, 2H), 4.53-4.26 (m, 1H), 4.26-3.89 (m,2H),3.89-3.65(m,1H),2.28(m,1H),2.04(m,1H),1.82-1.65(m,2H),1.66-1.43(m,7H),1.38(s ,4H), 1.19-1.01 (m,3H). LCMS-ESI ⁺ (m/z ^{): [M+H]+} _{Theoretical for C21H27N2O4} : _371.2 ; found: 370.8.

step 9

To a solution of 86-I (319 mg, 0.861 mmol) in EtOH (12 mL) was added hydrazine hydrate (0.17 mL, 3.494 mmol) at room temperature, and the resulting solution was stirred in a 70 °C bath. After 1.5 hours, the mixture was cooled to 0°C and diluted with diethyl ether (25 mL) before stirring at 0°C for 1 hour. The mixture was filtered, and the filtrate was concentrated. _The residue was dissolved in _CH2Cl2 and filtered to remove some insoluble material. The obtained filtrate was concentrated. The crude amine is obtained. LCMS-ESI ⁺ (m/z): [M ₊ H] ⁺ _calcd for _C13H25N2O2 : _241.2 ; found: 240.9.

After co-evaporating the crude amine with toluene, a mixture of crude amine 85-I (300 mg, 0.866 mmol) and NaHCO ₃ (150 mg, 1.845 mmol) in water (3 mL) and EtOH (3 mL) was stirred at room temperature. After 2 hours, the mixture was diluted with water and extracted with EtOAc (x2). After washing the extracts with water, the organic extracts were combined, dried ( _{Na2SO4 )} and concentrated. To a solution of the residue in _CH2Cl2 ( ₂ mL) was added 4N HCl in dioxane (6 mL). After 1.5 hours at room temperature, the solution was concentrated and co-evaporated with toluene. A mixture of the residue and DBU (0.65 mL, 4.347 mmol) in toluene (6 mL) was stirred at 100 °C. After 1 hour, additional DBU (0.65 mL, 4.347 mmol) was added and the mixture was stirred again at 100 °C. After 1 hour, additional DBU (0.65 mL, 4.347 mmol) was added and the mixture was stirred at 100 °C for an additional 2.5 hours. The mixture was diluted with _CH2Cl2 and washed with water containing ₃ mL of 1N HCl. The organic fractions were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography using EtOAc-20% MeOH/EtOAc as eluent to afford 86-J. ¹ H-NMR (400MHz, CDCl ₃ ) δ8.09(s, 1H), 7.70-7.62(m, 2H), 7.37-7.27(m, 3H), 5.48(d, J=9.9Hz, 1H), 5.16 (d,J=9.9Hz,1H),4.53(s,1H),4.38(m,2H),4.11(m,1H),3.97(dd,J=12.2,3.0Hz,1H),3.88(dt, J＝12.2, 3.0Hz, 1H), 2.63(d, J＝4.2Hz, 1H), 2.28(qd, J＝7.2, 3.1Hz, 1H), 2.00-1.88(m, 1H), 1.80-1.56(m ,2H),1.39(t,J=7.1Hz,3H),1.07(d,J=6.9Hz,3H),1.04(dd,J=5.0,2.5Hz,1H).LCMS-ESI ⁺ (m/z ): [M+H] ⁺ theoretical value for C ₂₄ H ₂₇ N ₂ O ₅ : 423.2; found value: 423.2.

Step 10

A mixture of 86-J (83 mg, 0.196 mmol) in THF (2 mL) and EtOH (2 mL) was stirred at room temperature while IN KOH (0.4 mL) was added. After 30 minutes, the reaction mixture was diluted with water and _washed with _CH2Cl2 . After acidifying the aqueous fraction with 1N HCl (0.45 mL), the product was extracted with _CH2Cl2 ( _x2 ). The combined extracts were dried ( _{Na2SO4 )} and concentrated to give the crude acid. LCMS-ESI ⁺ (m/z): [M ₊ H] ⁺ Calc: _C22H23N2O5 : _395.2 ; Found: _395.2 .

A mixture of crude acid (69 mg, 0.175 mmol), 2,4,6-trifluorobenzylamine (42 mg, 0.261 mmol) and HATU (106 mg, 0.279 mmol) in CH ₂ Cl ₂ (3 mL) was stirred at room temperature. The mixture was simultaneously added with N,N-diisopropylethylamine (DIPEA) (0.25 mL, 1.435 mmol). After 30 min, the reaction mixture was concentrated, and the residue was dissolved in EtOAc, washed with saturated aqueous _NH4Cl (x2), saturated aqueous _NaHCO3 (x2) and brine. After extracting the aqueous fraction with EtOAc, the two organic fractions were combined, dried ( _{Na2SO4 )} and concentrated. The residue was purified by flash chromatography using EtOAc-20% MeOH/EtOAc as eluent to afford 86-K. ¹ H-NMR (400MHz, CDCl ₃ ) δ10.40(t, J=5.7Hz, 1H), 8.40(s, 1H), 7.66-7.51(m, 2H), 7.36-7.29(m, 2H), 7.29 -7.23(m,1H),6.71-6.61(m,2H),5.36(d,J=10.0Hz,1H),5.18(d,J=10.0Hz,1H),4.73-4.58(m,2H), 4.53(s,1H),4.22-4.11(m,1H),4.03(dd,J＝12.4,3.1Hz,1H),3.81(dt,J＝12.3,3.1Hz,1H),2.68-2.59(m, 1H), 2.29(dddd, J=11.4, 7.1, 4.7, 2.4Hz, 1H), 1.94(ddd, J=13.5, 11.2, 4.6Hz, 1H), 1.88-1.67(m, 2H), 1.06(d, J=7.0Hz, 3H), 1.03-1.09(m, 1H). ¹⁹ F-NMR (376MHz, CDCl ₃ ) δ-109.14(ddd, J=15.2,8.7,6.2Hz,1F),-111.86(t,J=7.0Hz,2F).LCMS-ESI ⁺ (m/z) : [M+H] ⁺ Theoretical for C ₂₉ H ₂₇ F ₃ N ₃ O ₄ : 538.2; Found: 538.1.

step 11

86-K (61 mg, 0.113 mmol) was dissolved in trifluoroacetic acid (2 mL) at room temperature. After ₁ h, the solution was concentrated, and the residue was dissolved in _CH2Cl2 . After washing the solution with 0.1N HCl, the aqueous fraction was extracted with _CH2Cl2 ( _x2 ). The organic fractions were combined, dried ( _{Na2SO4 )} and concentrated. _The residue was purified by flash chromatography using _CH2Cl2-20 % MeOH in _CH2Cl2 as eluent to afford _compound 86. ¹ H-NMR (400MHz, CDCl ₃ ) δ12.02(s, 1H), 10.40(t, J=5.7Hz, 1H), 8.35(s, 1H), 6.63(t, J=8.1Hz, 2H), 4.62(d,J=5.7Hz,2H),4.59(s,1H),4.22(dd,J=12.2,3.5Hz,1H),4.13(t,J=11.9Hz,1H),4.05(dt,J =12.0,3.1Hz,1H),2.77-2.70(m,1H),2.31m,1H),2.09-1.93(m,1H),1.93-1.81(m,2H),1.10(ddd,J=13.9, 5.0,2.1Hz,1H),1.02(d,J=6.9Hz,3H). ¹⁹ F-NMR(376MHz,CDCl ₃ )δ-109.22(ddd,J=15.1,8.7,6.1Hz,1F),-112.05 (t, J = 6.9 Hz, 2F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ Theoretical for C ₂₂ H ₂₁ F ₃ N ₃ O ₄ : 448.2; Found: 448.3.

Example 87

Preparation of cis-5-aminotetrahydro-2H-pyran-3-ol

step 1

Benzyl (5-oxotetrahydro-2H-pyran-3-yl)carbamate (740 mg, 3.0 mmol) and cerium (III) chloride heptahydrate (1.12 g, 3.0 mmol) in 20 mL of methanol The solution was cooled to 0 °C, then sodium borohydride (120 mg, 3.2 mmol) was added portionwise. The reaction mixture was stirred at 0 °C for 45 minutes, then quenched by the slow addition of 1 mL of acetone, followed by stirring at room temperature for 3 hours. The reaction mixture was partitioned between water and dichloromethane, and the aqueous phase was extracted into dichloromethane followed by 2-butanol. The combined organic phases were dried over magnesium sulfate, filtered, concentrated, and the residue was purified by flash chromatography (0-100% EtOAc/hexanes) to afford the desired cis-((3R,5S)-5-hydroxytetrahydro -2H-pyran-3-yl)carbamate benzyl ester. ¹ H-NMR (400MHz, chloroform-d) δ7.39-7.26 (m, 5H), 6.06 (br s, 1H), 5.07 (s, 2H), 3.86-3.70 (m, 2H), 3.69-3.47 ( m, 4H), 2.00-1.89 (m, 1H), 1.76 (d, J=13.5Hz, 1H). The undesired trans isomer was also isolated.

step 2

To a solution of benzyl cis-((3R,5S)-5-hydroxytetrahydro-2H-pyran-3-yl)carbamate (290 mg, 1.16 mmol) in 5 mL of 1:1 DCM:EtOH was added 10 wt % Pd/C (255 mg). The mixture was stirred under balloon pressure hydrogen for 18 hours and the palladium was removed by filtration through celite, rinsing with ethanol. When the filtrate was concentrated, cis-5-aminotetrahydro-2H-pyran-3-ol was obtained and worked up as crude material.

Example 88

Preparation of Compound 88

'(2R,5S,13aR)-N-(3-Chloro-2-fluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13, 13a-Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Compound 88 was prepared in a manner similar to compound 15, using (3-chloro-2-fluorophenyl)methylamine instead of (4-fluorophenyl)methylamine. ¹ H-NMR (400MHz, chloroform-d) δ10.43 (br s, 1H), 8.34 (br s, 1H), 7.32-7.24 (m, 2H), 7.02 (t, J=7.9Hz, 1H), 5.36(d, J=9.4Hz, 1H), 5.30(s, 2H), 4.70(d, J=6.0Hz, 3H), 4.24(d, J=12.0Hz, 1H), 4.00(dd, J=12.7 ,9.5Hz,1H),2.18-1.96(m,4H),1.96-1.83(m,1H),1.60(dt,J＝12.4,3.1Hz,1H).LCMS-ESI ⁺ (m/z):C [M+H] ⁺ calcd for ₂₁ H ₁₉ ClFN ₃ O ₅ : 448.11; found: 448.2.

Example 89

Preparation of Compound 89

(2R,5S,13aR)-N-(2,5-Difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a- Octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Compound 89 was prepared in a manner similar to compound 15, using (2,5-difluorophenyl)methylamine instead of (4-fluorophenyl)methylamine. ¹ H-NMR (400MHz, chloroform-d) δ10.32(t, J=5.8Hz, 1H), 8.31(br s, 1H), 7.15-6.89(m, 2H), 6.86(d, J=8.5Hz ,1H),5.40(d,J=9.3Hz,1H),5.24(s,1H),4.67-4.51(m,3H),4.35-4.28(m,1H),3.99-3.90(m,1H), 2.16-1.85 (m, 5H), 1.60-1.50 (m, 1H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value of C ₂₁ H ₁₉ F ₂ N ₃ O ₅ : 432.14; Found value: 432.2.

Example 90

Preparation of compound 90

(1R,4S,12aR)-N-(3-Chloro-2-fluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a -Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 90 was prepared in a manner similar to compound 41, using (3-chloro-2-trifluorophenyl)methylamine instead of (2,4,6-trifluorophenyl)methylamine. ¹ H-NMR (400MHz, chloroform-d) δ9.22(s, 1H), 8.79(s, 1H), 7.39-7.28(m, 2H), 7.06(t, J=8.0Hz, 1H), 4.89( s,1H),4.70-4.56(m,3H),4.06-3.83(m,2H),3.04-2.88(m,1H),2.77(s,1H),1.97-1.58(m,6H).LCMS- ESI ⁺ (m/z): [ _M ^+H]+ _calcd for _{C21H19ClFN3O4} : _432.11 ; found: 432.2.

Example 91

Preparation of compound 91

(1R,4S,12aR)-7-Hydroxy-6,8-dioxo-N-(2,3,4-trifluorobenzyl)-1,2,3,4,6,8,12, 12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 91 was prepared in a similar manner to Compound 41, using (2,3,4-trifluorophenyl)methylamine instead of (2,4,6-trifluorophenyl)methylamine. ¹ H-NMR (400MHz, chloroform-d) δ10.25(s, 1H), 8.45(s, 1H), 7.10(d, J=5.1Hz, 1H), 6.90(d, J=8.7Hz, 1H) ,4.89(s,1H),4.63(s,2H),4.22(d,J=11.6Hz,1H),3.93-3.73(m,2H),2.71(s,1H),1.97-1.57(m,6H ). LCMS-ESI ⁺ ( _m /z): [ _{M +} H] ⁺ calcd for _C21H18F3N3O4 : _434.13 ; found: 434.2.

Example 92

Preparation of Compound 92

(1R,4S,12aR)-N-(4-Chloro-2-fluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a -Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 92 was prepared in a manner similar to compound 41, using (4-chloro-2-trifluorophenyl)methylamine instead of (2,4,6-trifluorophenyl)methylamine. ¹ H-NMR (400MHz, chloroform-d) δ10.28(s,1H),8.41(s,1H),7.29(s,1H),7.11-6.95(m,2H),4.85(s,1H), 4.57(s,2H),4.22(d,J=10.2Hz,1H),3.81(q,J=13.9,13.1Hz,2H),2.68(s,1H),1.99-1.50(m,6H).LCMS - ESI ⁺ (m/z): [M+H] ⁺ calcd for C ₂₁ H ₁₉ ClFN ₃ O ₄ : 432.11; found: 432.2.

Example 93

Preparation of compound 93

(1R,4S,12aR)-N-(2-Chloro-4,6-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8, 12,12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

step 1

A 5 mL microwave vial was charged with 2-bromo-1-chloro-3,5-difluorobenzene (540 mg, 2.4 mmol), cuprous cyanide (436 mg, 4.87 mmol), tetrakis(triphenylphosphine)palladium ( 63mg, 0.05mmol), sealed and evacuated/backfilled with nitrogen. To this was added 5 mL of degassed DMF. Heat the sealed vessel at 110 °C for 18 hours, dilute with ethyl acetate, and wash sequentially with 9:1 _NH4OH : _NH4Cl (aq) twice, 5% LiCl(aq) twice and brine Wash twice. Then, the organic phase was dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by flash chromatography (100% hexanes) to afford 2-chloro-4,6-difluorobenzonitrile. ¹ H-NMR (400 MHz, chloroform-d) δ 7.13 (dt, J=8.0, 1.9 Hz, 1H), 6.93 (td, J=8.5, 2.3 Hz, 1H).

step 2

To a solution of 2-chloro-4,6-difluorobenzonitrile (210 mg, 1.2 mmol) in 2.4 mL of THF was added a solution of 2M borane-DMS in THF (0.6 mL). The reaction mixture was stirred at reflux temperature for 18 hours, resulting in loss of all solvent. The solution was redissolved in 3 mL of THF, cooled to 0 °C, a 6M solution of HCl (aq) was added carefully, and the mixture was brought back to reflux for 30 min. The reaction mixture was cooled to 0 °C again and treated with 4M NaOH (aq). The aqueous phase was extracted with DCM, the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by flash chromatography (0-10% MeOH/DCM) to afford (2-chloro-4,6-difluorophenyl)methanamine. ¹ H-NMR (400MHz, chloroform-d) δ6.95(dt, J=8.3, 2.1Hz, 1H), 6.76(td, J=9.4, 2.5Hz, 1H), 3.94(d, J=1.9Hz, 2H).

Steps 3 and 4

At room temperature, stir 93-A (74 mg, 0.11 mmol), (2-chloro-4,6-difluorophenyl) methylamine (48.5 mg, 0.27 mmol), HATU (100 mg, 0.26 mmol) and N,N - A solution of diisopropylethylamine (0.1 mL, 0.57 mmol) in 1 mL of dichloromethane for 1 h, at which time complete disappearance of 93-A and formation of 93-B was observed by LCMS. TFA (0.65M) was added and the mixture was stirred at room temperature for 1 hour at which time 1 mL of DMF was added. Then, the reaction mixture was concentrated and purified by preparative HPLC (ACN/H ₂ O+0.1% TFA) to afford compound 93. ¹ H-NMR (400MHz, DMSO-d ₆ ) δ10.41(t, J=5.7Hz, 1H), 8.33(s, 1H), 7.41-7.26(m, 2H), 4.72-4.57(m, 3H) ,4.43(dd,J=12.5,3.6Hz,1H),3.94(t,J=12.4Hz,2H),3.77(dd,J=12.4,3.6Hz,3H),1.87-1.67(m,3H), 1.67-1.45(m, 2H), 1.43(d, J=10.4Hz, 1H).LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value of C ₂₁ H ₁₈ ClF ₂ N ₃ O ₄ : 450.10; measured value: 450.2.

Example 94

Preparation of Compound 94

(1R,4S,12aR)-N-Benzyl-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-bridge Methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

Compound 94 was prepared in a similar manner to Compound 41, using phenylmethylamine instead of (2,4,6-trifluorophenyl)methylamine. ¹ H-NMR (400MHz, chloroform-d) δ10.37(s, 1H), 8.26(s, 1H), 7.37-7.19(m, 5H), 4.55(d, J=4.8Hz, 1H), 4.34( d,J=5.7Hz,1H),4.23(d,J=9.8Hz,1H),4.09(d,J=28.2Hz,1H),3.78(d,J=10.9Hz,1H),3.64(d, J=13.2Hz, 1H), 3.14-3.01(m, 1H), 1.91-1.49(m, 4H). LCMS-ESI ⁺ (m/z): C ₂₁ H ₂₁ N ₃ O ₄ [M+H] ⁺ Theoretical value: 380.16; measured value: 380.2.

Example 95

Chiral tert-butyl 3-((1,3-dioxoisoindolin-2-yl)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 95-A and the preparation of 95-B

step 1

Racemic tert-butyl 3-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (285mg, 1.34mmol), triphenylphosphine (425mg, 1.62mmol ) and phthalimide (240 mg, 1.62 mmol) in 9 mL of THF at 0°C were added dropwise a solution of diisopropyl azodicarboxylate (0.35 mL, 1.8 mmol) in 1 mL of THF. The reaction mixture was allowed to warm to room temperature, stirred for 90 minutes, concentrated on silica, and purified by flash chromatography (0-25% EtOAc/hexanes) to give 3-((1,3-di Oxoisoindolin-2-yl)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester. LCMS-ESI ⁺ (m/z): [M ₊ H] ₊ ^calcd for _C19H23N2O4 : _343.2 ; found: 342.8.

step 2

Racemic 3-((1,3-dioxoisoindolin-2-yl)methyl)-2- Azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl ester (655 mg, 1.91 mmol) afforded chiral 95-A in enantiomerically enriched form (first eluting peak) and 95-B (second eluting peak). For 95-A: 144 mg, 98% ee (absolute stereochemistry unknown). For 95-B: 242 mg, 49% ee ((absolute stereochemistry unknown).

Example 96

Preparation of Compound 96

(1R,3R,11aS)-6-Hydroxy-5,7-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,5,7,11,11a-hexahydro -1H-1,3-methanopyrido[1,2-a]pyrrolo[1,2-d]pyrazine-8-carboxamide

step 1

To a solution of Intermediate 95-A (141 mg, 0.41 mmol, 98% ee, absolute stereochemistry unknown) in 9 mL of ethanol was added hydrazine hydrate (0.5 mL, 10.3 mmol) and stirred at 70 °C for 18 hours to give 96-A with unknown absolute stereochemistry. The solids were removed by filtration and the filtrate was concentrated and carried on as crude material.

step 2

A mixture of crude 96-A (0.41 mmol assumed), 96-B (430 mg, 1.25 mmol) and sodium bicarbonate (69 mg, 0.82 mmol) in 2 mL of water and 2 mL of ethanol was stirred at room temperature for 18 hours, which The reaction mixture was then diluted with water and extracted three times into ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The crude residue (222 mg) was dissolved in 1.5 mL of DCM, 4N HCl in dioxane (4 mL) was added and stirred at room temperature for 90 minutes. The mixture was concentrated to dryness and coevaporated with toluene. The crude residue and DBU (0.3 mL, 2.0 mmol) in 6 mL of methanol were stirred at 50 °C for 90 minutes. The reaction mixture was then concentrated on silica gel and purified by flash chromatography (0-10% MeOH/DCM) to afford 96-C. LCMS-ESI ⁺ (m/z): [M+H] ⁺ _calcd for _C22H22N2O5 : _395.16 ; found: _395.2 .

step 3

A mixture of 96-C (112 mg, 0.28 mmol), 1 M aqueous potassium hydroxide (1 mL), 4 mL methanol, and 4 mL THF was stirred at room temperature for 3 h at which time the mixture was diluted with dichloromethane and acidified by adding 1 M aqueous hydrogen chloride , and the organic phase was extracted into dichloromethane. The combined organics were dried, filtered, and concentrated from toluene. After drying under vacuum, the residue was suspended in 1.5 mL of DCM, and trifluorobenzylamine (62 mg, 0.38 mmol), HATU (220 mg, 0.58 mmol) and N,N-diisopropylethylamine ( DIPEA) (0.15 mL, 0.86 mmol). The reaction mixture was stirred at room temperature for 2 hours to afford 96-D, which was carried on to the next step as crude material.

step 4

Trifluoroacetic acid (1.7 mL, 22.2 mmol) was added to the crude reaction solution containing 96-D from the previous step, and the reaction mixture was stirred at room temperature for 90 minutes. Then, 1 mL of DMF was added, the reaction mixture was concentrated to ~1 mL, filtered and purified by preparative HPLC (ACN/water+0.1% TFA) to afford compound 96 (absolute stereochemistry unknown). ¹ H-NMR (400MHz, DMSO-d ₆ ) δ10.45-10.35 (m, 1H), 8.39 (s, 1H), 7.23-7.09 (m, 2H), 4.67 (dd, J=12.6, 4.8Hz, 2H), 4.53(d, J=5.5Hz, 2H), 4.20(dd, J=11.9, 3.8Hz, 1H), 4.05-3.95(m, 1H), 2.96-2.88(m, 1H), 2.16(d ,J=7.0Hz,1H),1.97(d,J=7.0Hz,1H),1.68-1.60(m,1H),1.53-1.45(m,1H).LCMS-ESI ⁺ (m/z):C [M+H] ⁺ calcd for ₂₀ H ₁₆ F ₃ N ₃ O ₄ : 420.12; found: 420.2.

Example 97

Preparation of compound 97

(1S,3S,11aR)-6-Hydroxy-5,7-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,5,7,11,11a-hexahydro -1H-1,3-methanopyrido[1,2-a]pyrrolo[1,2-d]pyrazine-8-carboxamide

Compound 97 (49% ee, absolute stereochemistry unknown) was prepared in a similar manner to compound 96, using intermediate 95-B (49% ee, absolute stereochemistry unknown) instead of the enantiomerically opposite intermediate 95-A ). ¹ H-NMR (400MHz, DMSO-d ₆ ) δ10.39(t, J=5.7Hz, 1H), 8.42(s, 1H), 7.25-7.13(m, 2H), 4.73-4.66(m, 2H) ,4.54(d,J=5.7Hz,2H),4.20(dd,J=12.3,3.9Hz,1H),4.01(t,J=12.4Hz,1H),2.93(dd,J=6.7,3.4Hz, 1H), 2.19-2.14(m, 1H), 1.97(d, J=8.3Hz, 1H), 1.65(dd, J=10.4, 7.9Hz, 1H), 1.49(dd, J=10.5, 7.7Hz, 1H ). LCMS-ESI ⁺ ( _m /z): [ _{M +} H] ⁺ calcd for _C20H16F3N3O4 : _420.12 ; found: 420.2.

Example 98

Preparation of Compound 98

(1S,4R,12aR)-3,3-Difluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4 ,6,8,12,12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

step 1

98-A (0.5 g, 1.87 mmol) was dissolved in DCM (20 mL) and cooled to 0 °C under nitrogen. Dess-Martin periodinane (1.59 g, 3.74 mmol) was added slowly. The mixture was stirred at room temperature for 2 h, quenched with a saturated aqueous solution (160 mL) of Na ₂ S ₂ O ₃ /NaHCO ₃ (7:1 ), and stirred vigorously until the two layers separated. The crude product was extracted twice with DCM. The combined organic layers were dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel with 0-20% MeOH/DCM to afford 98-B. ¹ H-NMR (400MHz, chloroform-d) δ4.34-4.05 (m, 1H), 3.97-3.75 (m, 1H), 3.69 (s, 3H), 2.89 (dd, J＝4.4, 2.1Hz, 1H ), 2.30-1.97(m, 3H), 1.56(d, J=11.3Hz, 1H), 1.35(s, 9H). LCMS-ESI ⁺ (m/z): [M+ of C ₁₃ H ₁₉ NO ₅ H] ⁺ theoretical value: 269.13; found value: 270.78.

step 2

A solution of 98-B (504 mg, 1.87 mmol) in DCM (15 mL) was stirred at 0 °C. DAST (1 ml) was added dropwise to the reaction mixture. After stirring overnight at room temperature, the reaction mixture was cooled back to 0 °C. Sat. NaHCO ₃ (10 mL) was added slowly. The mixture was extracted twice with DCM and dried _{over Na2SO4} . After concentration, the residue was purified by flash chromatography 0-50% EtOA c/hexanes to afford 98-C. ¹ H-NMR (400MHz, chloroform-d) δ4.45-4.18 (m, 1H), 3.85 (m, 1H), 3.72 (d, J = 1.5Hz, 3H), 2.72 (ddd, J = 5.1, 3.2 , 1.6Hz, 1H), 2.27-1.52(m, 4H), 1.41(d, J=21.9Hz, 9H). ¹⁹ F _- NMR (376MHz, chloroform-d) δ- _91.72--93.99 (m), -113.65--115.98(m) _{.LCMS -} ESI ⁺ (m/z):[ M+H] ⁺ theoretical value: 291.13; found value: 291.55.

step 3

98-C (476 mg, 1.634 mmol) in THF (20 mL) was stirred at 0° C. while 2.0 M LiBH ₄ in THF (2.4 mL, 4.8 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was quenched with ice and diluted with EtOAc and saturated _NH4Cl (some _H2 evolution). After separation of the two phases, the organic fraction was washed with brine, dried ( _{Na2SO4 )} and concentrated. The crude product of 98-D was used as such in the next step. LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value for C ₁₂ H ₁₉ F ₂ NO ₃ : 263.13; found value: 164.10.

step 4

In a bath at 0°C, 98-D (1.634mmol), phthalimide (0.36g, 2.45mmol) and PPh ₃ (0.855g, 3.26mmol) in THF (10mL) were stirred while adding DIAD (0.642 mL, 3.26 mmol). After the addition, the mixture was stirred at 0° C. for 30 minutes, then at room temperature for 16 hours. It was diluted with EtOAc and saturated _NH4Cl . After stirring for 5 minutes, the solid was filtered off and the two phases were separated. The organic phase was washed with brine, dried ( _{Na2SO4 )} and concentrated. The crude product was purified by flash chromatography using 0-50% EA/Hex as eluent to afford 98-E. ¹ H-NMR showed a mixture of two rotamers. ¹ H-NMR (400MHz, chloroform-d) δ7.89-7.80 (m, 2H), 7.78-7.66 (m, 2H), 5.02 (ddt, J=16.6, 12.5, 6.3Hz, 1H), 4.24 (d ,J＝71.8Hz,1H),4.10-3.92(m,1H),3.83-3.51(m,2H),2.46(s,1H),2.21-1.98(m,2H),1.87-1.62(m,2H ), 1.31(d, J=8.5Hz, 9H); ¹⁹ F-NMR (376MHz, chloroform-d) δ-91.22--93.58(m),-113.20--115.45(m).LCMS-ESI ⁺ (m /z ^{): [M+H]+} _{Calc for C20H22F2N2O4 : 392.15} ; found: 393.3.

step 5

To a solution of 98-E (696 mg, 1.774 mmol) in EtOH (10 mL) was added hydrazine hydrate (1 mL) at room temperature, and the resulting solution was stirred at room temperature for 2 hours. The mixture was diluted with diethyl ether (30 mL) and stirred at 0 °C for 60 minutes before being filtered. _The filtrate was concentrated, the residue was dissolved in _CH2Cl2 and filtered. The filtrate was concentrated and purified by flash chromatography on silica gel with 0-20% MeOH (0.2% TEA)/DCM to afford 98-F. ¹ H-NMR (400MHz, chloroform-d) δ4.91 (p, J = 6.2Hz, 1H), 4.29-3.97 (m, 1H), 3.36-2.93 (m, 2H), 2.49 (qt, J = 8.8 , 5.2Hz, 2H), 2.08 (dddd, J = 25.5, 14.0, 7.1, 4.9Hz, 1H), 1.89-1.49 (m, 4H), 1.41 and 1.21 (d, J = 6.2Hz, 9H). ¹⁹ F-NMR (376MHz, chloroform-d) δ-91.63--93.16(m), -113.11--115.08(m).LCMS-ESI ⁺ (m/z): C ₁₂ H ₂₀ F ₂ N ₂ O ₂ Theoretical value of [M+H] ⁺ : 262.15; found value: 262.8.

Steps 6, 7 and 8

A mixture of 98-G (375.8 mg, 1.55 mmol), 98-E (370 mg, 1.41 mmol) and NaHCO-3 (261 mg, 3.10 mmol) in water (5 mL) and EtOH (5 mL) was stirred at room temperature for 2 h . The mixture was diluted with brine and extracted with EtOAc (x2). The extracts were combined, dried (Na ₂ SO ₄ ), concentrated, and dried in vacuo to afford crude A. LCMS-ESI ⁺ (m/z): [M+H] ⁺ 591.59. To crude A (1.38 mmol) in _CH2Cl2 ( ₅ mL) was added 4N HCl in dioxane (5 mL). After 2 hours at room temperature, the mixture was concentrated to dryness. This was co-evaporated once with toluene and dried in vacuo to afford crude B. B (1.38 mmol + 0.442 mmol) and DBU (3 mL, 11 mmol) in anhydrous MeOH (15 mL) were stirred for 40 min in a 50 °C bath. The mixture was concentrated. The residue was purified by flash chromatography (80 g column) using 0-20% MeOH/DCM as eluent to afford 98-H. LCMS-ESI ⁺ (m/z): [M ₊ H] ⁺ Theoretical: _C23H22F2N2O5 : _444.15 ; Found: _445.36 (90%), 431.18 ( ₁₀ %).

Steps 9, 10 and 11

Using a method similar to Example 41, the remaining steps were performed to obtain the desired compound 98. ¹ H-NMR (400MHz, chloroform-d) δ10.29(d, J=6.1Hz, 1H), 8.34(s, 1H), 6.65(dd, J=8.7, 7.5Hz, 2H), 4.83(s, 1H), 4.72-4.58(m, 2H), 4.36-4.10(m, 2H), 4.05(t, J＝11.5Hz, 1H), 2.97(d, J＝4.4Hz, 1H), 2.49-2.08(m ,3H), 2.12-1.94(m,1H). ^{1 9} F-NMR (376MHz, chloroform-d) δ-92.08--93.57 (m, 1F), -108.92 (ddd, J=15.1, 8.8, 6.3Hz, 1F), -109.30--110.65 (m, 1F ), -112.16 (p, J=7.3Hz, 2F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ theoretical value of C ₂₁ H ₁₆ F ₅ N ₃ O ₄ : 469.11; measured value: 470.23.

Example 99

Preparation of compound 99

(1R,3S,4R,12aR)-7-Hydroxy-3-methyl-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4 ,6,8,12,12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

step 1

To a stirred solution of 99-A (1 g, 3.71 mmol) in THF (20 mL) was added a solution of Tebbe's reagent (0.5M in toluene, 14.85 mL, 7.42 mmol) dropwise at 0°C. After the addition, the brown solution was slowly warmed to room temperature and stirred at room temperature for 2 hours. The reaction was carefully quenched by the addition of saturated NaHCO ₃ solution at 0 °C, and the mixture was stirred at room temperature for 15 min. The mixture was filtered through celite and the filter cake was washed twice with ether and DCM (1:1). After separation of the layers, the organic layers were combined, concentrated in vacuo, and the residue was purified by column chromatography on silica gel with 0-50% EtOAc/hexanes to afford 99-B. ¹ H-NMR (400MHz, chloroform-d) δ5.06 (dt, J = 48.6, 2.6Hz, 1H), 4.73 (d, J = 7.0Hz, 1H), 4.42 (d, J = 61.8Hz, 1H) ,3.81(d,J=48.2Hz,1H),3.73(d,J=1.6Hz,3H),2.74(dd,J=9.4,4.4Hz,1H),2.38(ddt,J=13.5,4.5,2.5 Hz,1H),2.18-2.06(m,1H),1.99(dt,J=10.2,2.4Hz,1H),1.58(s,1H),1.42(d,J=25.5Hz,9H).LCMS-ESI ⁺ (m/z): [M ^+H]+ _calcd for _C14H21NO4 : _267.15 ; found: 267.65.

step 2

A mixture of 99-B (675 mg, 2.506 mmol) and 20% Pd(OH) ₂ /C (500 mg) in EtOH (50 mL) was stirred under H ₂ atmosphere. The mixture was filtered through celite, and the filtrate was concentrated to afford 99-C. ¹ H-NMR (400MHz, chloroform-d) δ4.23-3.99(m, 1H), 3.77-3.64(m, 4H), 2.55(d, J=4.8Hz, 1H), 2.14-1.86(m, 3H ),1.42(d,J=24.2Hz,9H),0.96(d,J=6.6Hz,3H),0.85(ddd,J=12.5,4.8,2.4Hz,1H).LCMS-ESI ⁺ (m/z ): [M+H] ⁺ Theoretical for C ₁₄ H ₂₃ NO ₄ : 269.16; Found: 269.69.

step 3

99-C (670 mg, 2.488 mmol) in THF (20 mL) was stirred at 0° C. while 2.0 M LiBH ₄ in THF (3.7 mL, 7.46 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was quenched with ice and diluted with EtOAc and saturated _NH4Cl (some _H2 evolution). After separation of the two phases, the organic fraction was washed with brine, dried ( _{Na2SO4 )} and concentrated. The crude alcohol 99-D was used as such in the next step. LCMS-ESI ⁺ (m/z): [ _M +H] ⁺ calcd for _C13H23NO3 : _241.17 ; found: 241.76.

Steps 4 and 5

Using a procedure similar to that in Example 41, steps 4 and 5 were performed to afford 99-F. LCMS-ESI ⁺ (m/z): [ _{M +} H] ⁺ _calcd for _C13H24N2O2 : 240.18; found: 241.2.

Steps 6, 7 and 8

Using a procedure similar to that in Example 41, steps 6, 7 and 8 were performed to afford 99-G. LCMS-ESI ⁺ (m/z): [ _M +H] ⁺ _calcd for _C24H26N2O5 : _422.18 ; found: 423.21.

Steps 9, 10 and 11

Using a method similar to Example 41, the remaining steps were performed to obtain the desired compound 99. ¹ H-NMR (400MHz, chloroform-d) δ11.71(s, 1H), 10.36(t, J=5.7Hz, 1H), 8.28(s, 1H), 6.63(t, J=8.1Hz, 2H) ,4.63(t,J=5.4Hz,3H),4.12(dd,J=12.3,3.5Hz,1H),3.83(t,J=12.3Hz,1H),3.67(dd,J=12.3,3.4Hz, 1H), 2.64-2.52(m, 1H), 2.30(ddq, J=10.5, 7.2, 3.6Hz, 1H), 2.13(td, J=12.1, 4.4Hz, 1H), 1.82-1.63(m, 2H) , 1.24 (d, J=3.3Hz, 1H), 1.04 (d, J=6.9Hz, 4H), 0.90-0.79 (m, 1H). ¹⁹ F-NMR (376MHz, chloroform-d) δ-109.20 (ddd, J = 15.0, 8.8, 6.2Hz), -112.03 (t, J = 7.0Hz). LCMS-ESI ⁺ (m/z): C ₂₂ [ _{M +} H] ⁺ calcd for _H20F3N3O4 : _447.14 ; found: 448.32.

Example 100

Preparation of Compound 100

(1R,4R,12aS)-N-(2,4-Difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a- Octahydro-1,4-oxoethylene (ethano)dipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

step 1

A 100-mL round bottom flask was charged with 100-A (2.0 g, 7.8 mmol) in THF (20 mL). The reaction mixture was cooled to 0 °C. Borane dimethyl sulfide (2N in THF, 17.6 mL) was added slowly. Then, the reaction mixture was stirred overnight at room temperature. The reaction mixture was cooled back to 0 °C. Methanol (8 mL) was added dropwise to quench the reaction. After concentration, the residue was purified by CombiFlash (40 g column, cartridge used) using hexane-EA as eluent to give 100-B. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 242.

step 2

A 100-mL round bottom flask was charged with 100-B (1.8 g, 7.4 mmol), triphenylphosphine (4.3 g, 16.2 mmol) and phthalimide ( 1.8g, 12.2mmol). Then, the reaction mixture was cooled to 0 °C while stirring. DIAD (3.2 mL, 16.2 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred overnight at room temperature. After concentration, the residue was purified by CombiFlash (80 g column, cartridge used) using hexane-EA as eluent to afford 100-C. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 371.

step 3

To a solution of 100-C (2.5 g, 6.8 mmol) in EtOH (50 mL) was added hydrazine monohydrate (1.7 mL). The reaction mixture was heated to 70°C while stirring for 3 hours. After the solids were removed by filtration, the filtrate was concentrated to afford 100-D. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 241.

step 4

A 100-mL round bottom flask (rbf) was charged with 100-D (1.6 g, 6.7 mmol) and 100-E (2.3 g, 6.7 mmol) in ethanol (30 mL). Sodium bicarbonate (1.2 g, 1.4 mmol) in water (30 mL) was added to the reaction mixture. Then, the reaction mixture was stirred overnight at room temperature. The mixture was diluted with EA (200 mL) and washed with water (2x). The aqueous fraction was extracted with EA (1x), and the organic fractions were combined, dried ( _{Na2SO4 )} and concentrated. Crude 100-F was used in the next step without further purification. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 569.

step 5

100-F (3.7 g, 6.5 mmol) in 4N HCl/dioxane (38 mL) was charged to 100-mL of rbf. Then, the reaction mixture was stirred at room temperature for 1 hour. After concentration, 3.2 g of the intermediate were obtained. This intermediate and DBU (5.1 g, 33.8 mmol) were dissolved in toluene (100 mL). The reaction mixture was heated to 110°C while stirring for 1 hour. After concentration, the residue was purified by CombiFlash (80 g column, cartridge used) using hexane-EA as eluent to give 100-G. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 423.

step 6

100-G (2.0 g, 4.7 mmol) in THF (20 mL) and MeOH (20 mL) was charged in 100-mL of rbf. 1N KOH (18.9 mL) was added to the reaction mixture. Then, the reaction mixture was stirred at room temperature for 1 hour, and the reaction mixture was acidified by adding 1N HCl (18.9 mL). After concentration, the residue was coevaporated with toluene (3x). Crude acid (0.28g, 0.72mmol), 2,4-difluorobenzylamine (0.2g, 1.44mmol), N,N-diisopropylethylamine (DIPEA) (0.47g, 3.6mmol) and HATU (0.55 g, 1.44 mmol) was dissolved in DCM (20 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EA (100 mL), washed with saturated NaHCO ₃ (2x), saturated NH ₄ Cl (2x), and dried over Na ₂ SO ₄ . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to afford 100-H. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 520.

step 7

50-mL of rbf was charged with 100-H (0.36 g, 0.69 mmol) in TFA (5 mL). The reaction mixture was stirred for 30 minutes at room temperature. After concentration, the crude material was purified by column chromatography on silica gel with EtOAc-MeOH to afford compound 100. ¹ H-NMR (400MHz, chloroform-d) δ12.25(m, 1H), 10.47(t, J=5.9Hz, 1H), 8.30(s, 1H), 7.58-7.29(m, 1H), 6.98- 6.50(m,2H),4.62(dd,J=14.8,4.9Hz,3H),4.22(t,J=12.2Hz,1H),4.14-4.07(m,1H),3.96(dd,J=12.2, 3.1Hz, 1H), 2.26-1.44(m, 9H). ¹⁹ F-NMR (376MHz, chloroform-d) δ-112.38 (t, J=7.7Hz), -114.78 (q, J=8.5Hz). LCMS-ESI ⁺ (m/z): Found: 430.

Example 101

Preparation of Compound 101

(1R,4R,12aS)-7-Hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12, 12a-Octahydro-1,4-ethanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

step 1

101-A (0.3 g, 0.72 mmol) in THF (2 mL) and MeOH (2 mL) was charged to 100-mL of rbf. 1N KOH (2.1 mL) was added to the reaction mixture. Then, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified by adding 1N HCl (2.1 mL). After concentration, the residue was coevaporated with toluene (3x). The crude acid (0.72mmol), 2,4,6-trifluorobenzylamine (0.23g, 1.44mmol), N,N-diisopropylethylamine (DIPEA) (0.47g, 3.6mmol) and HATU ( 0.55 g, 1.44 mmol) was dissolved in DCM (20 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EA (100 mL), washed with saturated NaHCO ₃ (2x), saturated NH ₄ Cl (2x), and dried over Na ₂ SO ₄ . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtOAc to afford 101-B. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 538.

step 2

50-mL of rbf was charged with 101-B (0.36 g, 0.67 mmol) in TFA (5 mL). The reaction mixture was stirred for 30 minutes at room temperature. After concentration, the crude material was purified by column chromatography on silica gel with EtOAc-MeOH to afford compound 101. ¹ H-NMR (400MHz, chloroform-d) δ12.11(s, 1H), 10.40(t, J=5.8Hz, 1H), 8.28(s, 1H), 6.91-6.39(m, 2H), 4.62( ddd, J=25.0, 6.5, 2.8Hz, 3H), 4.21(t, J=12.2Hz, 1H), 4.09(dd, J=12.5, 3.0Hz, 1H), 3.93(dd, J=12.2, 3.1Hz , 1H), 2.35-1.39 (m, 9H). ¹⁹ F NMR (376 MHz, chloroform-d) δ -112.38 (t, J = 7.7 Hz), - 114.78 (q, J = 8.5 Hz). LCMS-ESI ⁺ (m/z): Found: 448.

Example 102

Preparation of compound 102

(1S,4S,12aR)-7-Hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12, 12a-Octahydro-1,4-ethanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

step 1

A 100-mL round bottom flask was charged with 102-A (2.0 g, 7.8 mmol) in THF (20 mL). The reaction mixture was cooled to 0 °C. Borane dimethyl sulfide (2N in THF, 17.6 mL) was added slowly. Then, the reaction mixture was stirred overnight at room temperature. The reaction mixture was cooled back to 0 °C. Methanol (8 mL) was added dropwise to quench the reaction. After concentration, the residue was purified by CombiFlash (40 g column, cartridge used) using hexane-EA as eluent to afford 102-B. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 242.

step 2

100-mL of rbf was charged with 102-B (1.8 g, 7.4 mmol), triphenylphosphine (4.3 g, 16.2 mmol) and phthalimide (1.8 g, 12.2 mmol). Then, the reaction mixture was cooled to 0 °C while stirring. DIAD (3.2 mL, 16.2 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred overnight at room temperature. After concentration, the residue was purified by CombiFlash (80 g column, cartridge used) using hexane-EA as eluent to afford 102-C. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 371.

step 3

To a solution of 102-C (2.5 g, 6.8 mmol) in EtOH (50 mL) was added hydrazine monohydrate (1.7 mL). The reaction mixture was heated to 70°C while stirring for 3 hours. After the solids were removed by filtration, the filtrate was concentrated to afford 102-D. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 241.

step 4

100-mL of rbf was charged with 102-D (1.6 g, 6.7 mmol) and 102-E (2.3 g, 6.7 mmol) in ethanol (30 mL). Sodium bicarbonate (1.2 g, 1.4 mmol) in water (30 mL) was added to the reaction mixture. Then, the reaction mixture was stirred overnight at room temperature. The mixture was diluted with EA (200 mL) and washed with water (2x). The aqueous fraction was extracted with EA (1x), the organic fractions were combined, dried ( _{Na2SO4 )} and concentrated. Crude material 102-F was used in the next step without further purification. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 569.

step 5

100-mL of rbf was charged with 102-F (3.7 g, 6.5 mmol) in 4N HCl/dioxane (38 mL). Then, the reaction mixture was stirred at room temperature for 1 hour. After concentration, 3.2 g of the intermediate were obtained. This intermediate and DBU (5.1 g, 33.8 mmol) were dissolved in toluene (100 mL). The reaction mixture was heated to 110°C while stirring for 1 hour. After concentration, the residue was purified by CombiFlash (80 g column, cartridge used) using hexane-EA as eluent to afford 102-G. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 423.

step 6

102-G (0.3 g, 0.72 mmol) in THF (2 mL) and MeOH (2 mL) was charged in 100-mL of rbf. 1N KOH (2.1 mL) was added to the reaction mixture. Then, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified by adding 1N HCl (2.1 mL). After concentration, the residue was coevaporated with toluene (3x). The crude acid (0.72mmol), 2,4,6-trifluorobenzylamine (0.23g, 1.44mmol), N,N-diisopropylethylamine (DIPEA) (0.47g, 3.6mmol) and HATU ( 0.55 g, 1.44 mmol) was dissolved in DCM (20 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EA (100 mL), washed with sat. NaHCO ₃ (2x), sat. NH ₄ Cl (2x), and dried over Na ₂ SO ₄ . After concentration, the crude material was purified by column chromatography on silica gel with hexane-EtO Ac to afford 102-H. LCMS-ESI ⁺ (m/z): [M+H] ⁺ Found: 538.

step 7

50-mL of rbf was charged with 102-H (0.36 g, 0.67 mmol) in TFA (5 mL). The reaction mixture was stirred for 30 minutes at room temperature. After concentration, the crude material was purified by column chromatography on silica gel with EtOAc-MeOH to afford compound 102. ¹ H-NMR (400MHz, chloroform-d) δ12.13(s, 1H), 10.40(t, J=5.8Hz, 1H), 8.28(s, 1H), 6.64(t, J=8.1Hz, 2H) ,4.89-4.41(m,3H),4.22(t,J=12.2Hz,1H),4.09(dd,J=12.3,3.1Hz,1H),3.95(dd,J=12.1,4.1Hz,1H), 2.45-1.60(m,9H) ^.19F -NMR(376MHz,chloroform-d)δ-109.26(ddd,J=15.1,8.8,6.3Hz),-111.99(t,J=6.9Hz).LCMS-ESI ⁺ (m/z): Found: 448.

Example 103

Preparation of compound 103

(1R,4R,12aR)-2,3-Difluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4 ,6,8,12,12a-Octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

step 1

In a dry ice/acetone bath, (1R,3R,4R,5R,6S)-5,6-dihydroxy-2-((S)-1-phenylethyl)-2-azabicyclo[2.2 .1] A solution of methyl heptane-3-carboxylate (2.0 g, 6.9 mmol) in DCM (27 mL) was cooled to -78 °C. To this solution was added DAST (2.18 mL, 16.48 mmol) via a plastic tipped pipette. The solution was stirred at -78°C for 30 minutes, after which it was removed from the bath, warmed slowly to room temperature, and stirred at room temperature for 1 hour. The reaction was quenched by slowly adding the reaction mixture to a stirred solution of saturated sodium bicarbonate (150 mL) via a plastic-tipped pipette. The layers were separated and the aqueous layer was back extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (7-28% ethyl acetate/hexanes) to afford 103-A. ¹ H-NMR (400MHz, chloroform-d) δ7.43-7.16(m, 5H), 5.01-4.60(m, 2H), 3.85(q, J=7.1, 6.6Hz, 1H), 3.55(s, 2H ),3.53-3.42(m,2H),2.76(dq,J＝5.1,2.0Hz,1H),2.19-2.07(m,1H),2.03-1.88(m,1H),1.39(d,J＝6.7 Hz, 3H).

Steps 2 and 3

To a solution of 103-A (0.96 g, 3.24 mmol) in ethanol (36.01 mL) and 1.25M HCl-ethanol (4.09 mL) was added 20% PdOH/C (1.14 g, 1.62 mmol) under hydrogen atmosphere, The suspension was stirred for 22 hours. After filtration through celite, the filter cake was washed with EtOH, and the filtrate was concentrated to dryness in vacuo to give the crude deprotected product, assumed to be 3.24 mmol, which was used in the next step. LCMS-ESI ⁺ (m/z): [M ₊ H] ⁺ Calc: _C8H12F2NO2 : _192.08 ; Found: _192.110 .

To the crude residue (0.62 g, 3.24 mmol) and di-tert-butyl dicarbonate (1.06 g, 4.86 mmol) in 2-methyltetrahydrofuran (32.43 mL) was added N,N-diisopropylethylamine ( 0.56mL, 0mol). Upon completion, the reaction mixture was diluted with water, extracted into EtOAc (2x), and the organic fractions were washed with water, combined, dried ( _{Na2SO4 )} and concentrated. The residue was purified by silica column chromatography (0-55% EtOAc/hexanes) to afford 103-B. ¹ H-NMR (400MHz, chloroform-d) δ5.12-5.01 (m, 1H), 4.92 (s, 1H), 4.49 (s, 1H), 4.14 (d, J = 14.7Hz, 1H), 3.75 ( s,3H),2.91(s,1H),2.24-1.98(m,2H),1.47(s,5H),1.38(s,5H).LCMS-ESI ⁺ (m/z):[M+H] ⁺ Theoretical value: C ₁₃ H ₂₀ F ₂ NO ₄ : 292.13; found value: 291.75.

step 4

A solution of 103-B (0.68 g, 2.33 mmol) in THF (15 mL) was stirred in an ice bath while 1.0 M LiBH ₄ in THF (4.65 mL) was added and the resulting mixture was stirred at 0 °C for 30 min , which at this point was shown to be complete by TLC. The reaction mixture was carefully treated with water (0.3 mL), then NaOH (-15%, 3.5M, 0.3 mL) and finally additional water (0.9 mL). The mixture was stirred at room temperature for 15 minutes, and the ppt formed was filtered, washed with ether, and the supernatant concentrated to afford 103-C. ¹ H-NMR (400MHz, chloroform-d) δ4.83(s, 1H), 4.56(d, J=10.5Hz, 1H), 4.37(s, 1H), 3.78-3.47(m, 3H), 2.76( s,1H), 2.36-2.18(m,1H), 2.17-1.98(m,1H), 1.55(s,1H), 1.48(s,9H).

Steps 5 and 6

A mixture of 103-C (0.59 g, 2.25 mmol), phthalimide (0.53 g, 3.6 mmol) and triphenylphosphine (1.3 g, 4.95 mmol) in THF (11 mL) was placed in an ice bath cool down. Diisopropyl azodicarboxylate (0.97 mL, 4.95 mmol) was added. The mixture was then allowed to warm to room temperature and stirred for 14 hours, then concentrated in vacuo. The residue was dissolved in ether and stirred for 1 hour, then the solid was filtered off and the filtrate was concentrated. The residue was purified by silica column chromatography (10-31-91% EtOAc/hexanes) to afford the protected amino compound (assumed 2.25 mmol of product). LCMS-ESI ⁺ (m/z ^{): [M+H]+} _{calcd for C20H23F2N2O4 : 393.15} ; found: 392.77.

A solution of the protected amino compound (0.88 g, 2.25 mmol) and hydrazine hydrate (0.46 mL, 9.52 mmol) in ethanol (22 mL) was stirred at 60 °C for 2 hours. The reaction mixture was cooled in an ice bath, diethyl ether (10 mL) was added, and the mixture was stirred for 30 min. The solid formed was filtered off, and the filtrate was concentrated to dryness in vacuo to afford 103-D. ¹ H-NMR (400MHz, chloroform-d) δ5.17-4.61(m,2H),4.37(s,1H),3.80(s,1H),3.11-2.77(m,1H),2.01(s,2H ),1.87(s,1H),1.83(d,J=7.4Hz,1H),1.46(s,9H),1.30(d,J=6.4Hz,1H),1.27(d,J=6.3Hz,3H ). LCMS-ESI ⁺ (m/z ^{): [M+H]+} _{Calc for C12H20F2N2O2 : 263.15} ; found: 262.86.

Steps 7, 8 and 9

Compound 103 was prepared in a manner similar to compound 60, using 103-D instead of 41-E, and (2,4,6-trifluorophenyl)methylamine instead of (2,3-dichlorophenyl)methylamine . Single diastereomers are produced. The stereochemistry of fluorine is unknown. ¹ H-NMR (400MHz, chloroform-d) δ8.08(s, 1H), 6.46-6.27(m, 2H), 4.95(d, J=53.5Hz, 1H), 4.65(d, J=54.9Hz, 1H), 4.45(s, 1H), 4.33(d, J=5.6Hz, 2H), 3.84(t, J=3.6Hz, 2H), 2.75(s, 1H), 2.28(p, J=1.9Hz, 2H), 2.20(s, 1H), 1.91(dd, J＝33.3, 15.2Hz, 1H), 0.95(s, 1H).LCMS-ESI ⁺ (m/z): C ₂₁ H ₁₇ F ₅ N ₃ O [M+H] ⁺ Theoretical for ₄ : 470.11; Found: .470.13.

Antiviral Assay

Example 104

Antiviral Assay in MT4 Cells

For antiviral assays using MT4cells, in each well of a 384-well assay plate, 0.4 μL of a 189X test concentration of a 3-fold serially diluted compound in DMSO was added to 40 μL of cell growth medium (RPMI 1640, 10% FBS , 1% penicillin/streptomycin, 1% L-glutamine, 1% HEPES) (10 concentrations), in quadruplicate.

Incubate a 1 mL aliquot of ² x 106 MT4 cells at 37 °C with 25 µL (MT4) of cell growth medium (mock-infected) or fresh 1:250 dilution of HIV-IIIb concentrated ABI stock (for MT4 cells: 0.004moi) were preinfected for 1 hour and 3 hours respectively. Infected and uninfected cells were diluted in cell growth medium and 35 μL of 2000 (for MT4) cells were added to each well of the assay plate.

Then, the assay plate was incubated in a 37°C incubator. After 5 days of incubation, 25 μL of 2X concentrated CellTiter-Glo ^™ reagent (Catalog #G7573, Promega Biosciences, Inc., Madison, WI) was added to each well of the assay plate. Cell lysis was performed by incubating at room temperature for 2-3 min, followed by chemiluminescence reading using an Envision reader (PerkinElmer).

Compounds of the invention demonstrated antiviral activity in this assay, as described in Table 1 below. Therefore, the compounds of the present invention can be used to treat the proliferation of HIV virus, treat AIDS, or delay the onset of AIDS or ARC symptoms.

Table 1

Example 105

Human PXR Activation Assay

Luciferase reporter gene assay: A stably transformed tumor cell line (DPX2) was plated in 96-well microtiter plates. DPX2 cells have a human PXR gene (NR1I2) and a luciferase reporter gene, XREM and PXRE, linked to two promoters identified in the human CYP3A4 gene. Cells were treated with six concentrations of each compound (0.15-50 [mu]M) and incubated for 24 hours. The number of viable cells is determined and reporter gene activity is assessed. Positive control: rifampicin in 6 concentrations (0.1-20 μM). The %Emax relative to the maximum fold induction of RIF at 10 or 20 μM is the theoretical value of the test compound according to the following equation, adjusted for the DMSO background: %Emax=(fold induction−1)/(maximum of RIF-1 Fold induction) × 100%.

Table 2

Example 106

OCT2 inhibition assay

Dose-Dependent Inhibition of ^OCT2 -Mediated Uptake of Test Compounds by the Model Substrate C-Tetraethylammonium (TEA) in 7 Concentrations from 0.014 μM to 10 μM in Wild-Type and OCT2-Transfected MDCKII Cells .

MDCKII cells were maintained in an incubator set at 37°C, 90% humidity, and 5% _CO with a minimum essential culture of 1% Pen/Strep, 10% fetal calf serum, and 0.25 mg/mL hygromycin B base (MEM). 24 hours prior to the assay, medium containing 5 mM sodium butyrate was added to the MDCKII cells in flasks and the cells were grown to 80-90% confluency. On the day of the assay, cells were trypsinized and resuspended in Krebs-Henseleit buffer (KHB), pH 7.4, at 5×10 ⁶ million cells/mL. Cells were pre-incubated in assay plates for 15 minutes prior to addition of test compound or matrix.

Test compounds were serially diluted in DMSO and then spiked (2 μL) into 0.4 mL of KHB buffer containing wild-type or OCT2-transfected cells and incubated for 10 minutes. The assay was started by adding 0.1 mL of 100 μM ¹⁴ C-TEA in KHB buffer (20 μM final concentration after mixing). Concentrations of TEA are based on Km. After 10 minutes of incubation, the assay mixture was quenched by adding 0.5 mL of ice-cold IX PBS buffer. Then, the samples were centrifuged at 1000 rpm for 5 minutes, and the supernatant was removed. Repeat the rinse step 4 times with ice-cold PBS. Finally, the cell pellet was lysed with 0.2N NaOH and allowed to stand at room temperature for at least 30 min to ensure complete dissolution. Samples were then counted on a liquid scintillation counter and dpm counts were used for the calculations described below. Inhibition % was calculated as follows: Inhibition % = [1-{[OCT2] _i- [WT] _ni }/{[OCT2] _{ni-[WT] ni }} ]*100, where [OCT2] _i represents OCT2 cells in dpm counts in the presence of test compounds, [OCT2] _ni represents dpm counts in OCT2 cells in the absence of test compounds, and [WT] _ni represents dpm counts in wild-type cells in the absence of test compounds.

table 3

The data in Tables 1, 2 and 3 represent the mean values over time for the respective assays for each compound. For some compounds, multiple assays have been performed over the course of the program. Therefore, the data reported in Tables 1, 2 and 3 include the data reported in the priority document, as well as the data from the assays performed during the intervention.

Example 107

Pharmacokinetic Analysis Following Oral or Intravenous Administration to Beagle Dogs

Pharmacokinetic analysis of various test compounds was performed following intravenous or oral administration to beagle dogs.

For pharmacokinetic analysis of intravenously administered compounds, test compounds were formulated in 5% ethanol, 55% PEG 300, and 40% water at 0.1 mg/mL for IV infusion. For pharmacokinetic analysis of orally administered compounds, test compounds were formulated in an aqueous suspension of 0.1% Tween 20, 0.5% HPMC LV100 in Di Water at 1 mg/kg.

Each drug group consisted of 3 male, adult (non-naive) purebred Beagle dogs. At the time of dosing, animals weighed between 10 and 13 kg. Animals were fasted overnight prior to dosing and up to 4 hours after dosing. For intravenous dosing studies, the test articles were administered to the animals by intravenous infusion over 30 minutes. The infusion rate was adjusted according to the body weight of each animal to deliver a dose of 0.5 mg/kg. For studies with oral dosing, the test article is dosed to deliver a dose of 1 mg/kg based on the body weight of each animal.

For pharmacokinetic analysis of intravenously administered compounds, serial venous blood samples were taken from each animal at 0, 0.250, 0.483, 0.583, 0.750, 1.00, 1.50, 2.00, 4.00, 8.00, 12.0, and 24.0 hours after dosing (approximately 1 mL each). Blood samples were collected into Vacutainer ^™ tubes containing EDTA-K2 as an anticoagulant and immediately placed on wet ice until centrifugation for plasma. Concentrations of test compounds in plasma were measured using LC/MS/MS methods. A 100 μL aliquot of each plasma sample was added to a clean 96-well plate and added to 400 μL of cold acetonitrile/internal standard solution (ACN)/(ISTD). After protein precipitation, a 110 μL aliquot of the supernatant was transferred to a clean 96-well plate and diluted with 300 μL of water. A 25 μL aliquot of the above solution was injected into a TSQQuantum Ultra LC/MS/MS system utilizing a Hypersil Gold C ₁₈ HPLC column (50×3.0 mm, 5 μm; Thermo-Hypersil Part # 25105-053030). An Agilent 1200 series binary pump (P/N G1312A Bin Pump) was used for elution and separation, and a HTSPal autosampler (LEAP Technologies, Carrboro, NC) was used for sample injection. A TSQ Quantum Ultra triple quadrupole mass spectrometer (Thermo Finnigan, San Jose, CA) was used in selective reaction monitoring mode. Liquid chromatography was performed using two mobile phases: mobile phase A containing 1% acetonitrile in 2.5 mM ammonium formate in water, pH 3.0; and mobile phase B containing 90% acetonitrile in 10 mM ammonium formate, pH 4.6. Noncompartmental pharmacokinetic analyzes were performed on plasma concentration-time data. The resulting data are shown in the first 3 columns of Table 4. In Table 4, CL refers to clearance, which characterizes the rate at which a drug is cleared from plasma. The lower the drug clearance rate, the longer the elimination half-life in vivo. V _ss refers to the steady state volume of distribution and indicates how well the drug is distributed in the tissue. The larger the Vss, the longer the elimination half-life in vivo. MRT refers to mean residence time, which is a measure of the average time a molecule exists in the body.

For pharmacokinetic analysis of orally administered compounds, serial venous blood samples (approximately 0.3 mL each ). In a manner similar to the venous studies described above, blood samples were collected, prepared and analyzed. Noncompartmental pharmacokinetic analysis was performed on the plasma concentration-time data. The resulting data are shown in the last 3 columns of Table 4. In Table 4, F (%) refers to oral bioavailability. _Cmax refers to the peak plasma concentration of a compound following administration. AUC refers to the area under the curve and is a measure of the total plasma exposure of the indicated compound.

Table 4

All US patents, US patent application publications, US patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned in this specification are hereby incorporated by reference in their entirety to the extent they are not inconsistent with this specification.

From the foregoing it will be appreciated that, while specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the invention is not to be limited except by the appended claims.

Claims (18)

1. A compound having the following formula (I): or its stereoisomer or pharmaceutically acceptable salt, in: X is -O-; W is -CHZ ² -; Wherein Z ¹ and Z ² are combined to form -L-, wherein L is -C(R ^a ) ₂ C(R ^a ) ₂ -; Z ⁴ is -CH ₂ -; Y ¹ and Y ² are each independently hydrogen, C _1-3 alkyl or C _1-3 haloalkyl; R is phenyl substituted with ^one to three halogens; and Each R ^a is independently hydrogen, halogen, hydroxy, or C _1-4 alkyl. 2. The compound of claim 1, having the following formula (II-A): Wherein X, L and R ¹ are as defined in claim 1. 3. The compound of any one of claims 1-2, wherein each ^Ra is hydrogen. 4. The compound of any one of claims 1-3, wherein ^Y1 and ^Y2 are each independently hydrogen, methyl or trifluoromethyl. 5. The compound of any one of claims 1-4, wherein R ¹ is substituted with three halogens. 6. The compound of claim ⁵ , wherein R1 is 2,4,6-trifluorophenyl or 2,3,4-trifluorophenyl. 7. The compound of claim ⁶ , wherein R1 is 2,4,6-trifluorophenyl. 8. The compound of claim 1 selected from the group consisting of: 9. A compound which is: 10. A pharmaceutical composition comprising the compound: Or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient. 11. A pharmaceutical composition comprising a compound according to any one of claims 1-9 or a stereoisomer or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient. 12. The pharmaceutical composition of claim 10 or 11, further comprising one or more additional therapeutic agents. 13. The pharmaceutical composition of claim 12, wherein the one or more additional therapeutic agents are anti-HIV agents. 14. The pharmaceutical composition of claim 13, wherein the one or more additional therapeutic agents are selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, reverse HIV nucleotide inhibitors of logase, and combinations thereof. 15. A method of treating an HIV infection in a human having an infection or at risk of having an infection by administering to said human a therapeutically effective amount of a compound according to any one of claims 1-9 or claim 10-14 pharmaceutical compositions. 16. Use of a compound according to any one of claims 1-9 or a pharmaceutical composition according to claims 10-14 for the treatment of HIV infection in a human having or at risk of having the infection. 17. A compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, for use in medical therapy. 18. A compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, for use in the therapeutic treatment of HIV infection.